CONTEMPORARY REVIEW OF THERAPEUTIC BENEFITS OF THE AMINO ACID TAURINE

Today, a greater range of care, reflecting differing philosophies on medical approaches, is widely available. At one end of the spectrum, conventional (allopathic) physicians utilize strictly standard textbook diagnostics and treatment protocols. At the other end, health practitioners (licensed, but not physicians) practice all sorts of treatments dubbed "alternative" -- from approaches less grounded in scientific basis (such as aromatherapy, homeopathy, folk medicine, and yoga) to those with sound research evidence (biofeedback, dietary modification, exercise, lifestyle changes, and vitamin supplementation). Alternative medicine is also referred to as complementary care. Integrative medicine merges the complementary preventative treatment philosophy with conventional medicine, most notably its proven diagnostic protocols (including blood work, lab testing and radiological and computerized assessments). Integrative care is 'body smart' in its enlightened multi-modal scope.

Orthomolecular medicine, based on the tenet of preventing and treating disease by providing the body with the optimal amounts of substances which are naturally found in the body, is the golden cornerstone of integrative medicine as it is practiced today. Employing natural substances including vitamins, minerals, trace elements, amino acids, fatty acids, and phytonutrients (substances derived from plant sources) in optimal supplemental quantities can produce efficacious therapeutic results. Yet, nutritional medicine is only as good as its weakest link. Much like teamwork, "one nutrient … added as a supplement to a food can bring no favorable effect unless the food contains some of all the other nutrients or unless they are available from the reserves of the person being nourished" (1). Hence, if you faithfully take your antioxidant vitamins, your B-complex, dash of gingko and splash of omega-3 oils, yet fail to address (or even know about) a deficiency elsewhere in the nutritional balance that ensures optimal body performance, you are only meeting part of your health needs. More importantly, only a health care provider properly trained in nutritional science can design a program suitable for you, because s/he has the expertise to choose and interpret the diagnostic tests that correlate with your physical exam. Then, and only then, can a customized plan of nutrient supplements, coupled with dietary, lifestyle and behavioral changes (and medicine if necessary) be properly devised so that it greatly augments the quality of your life.

Physicians pledge to do no harm to their patients when they are initiated into the practice of medicine. The optimal delivery of medical care is a fusion of elements -- a synergistic use of a broad range of therapeutic modalities substantiated by medical literature and evidence-based medicine that yield a sound treatment approach. "Full spectrum medicine" fuses the diversity of medical approaches to reduce symptoms and signs of illnesses and offer preventive approaches to ensure wellness. Such delivered care is:

Dynamic: recognizing the changing needs of the body during its response to care, customizing each patient’s program, and is proactive in monitoring the outcome
Synergistic: yielding the benefits of combining several modes of care simultaneously that synchronize with the body, thus exceeding the results of each modality when used independently
Integrated: providing each patient a harmonious and well-executed plan that forms a complete approach to achieving and maintaining optimal health

We will continue to witness vast and dramatic medical landmarks well into the new millennium. Gene and telomerase therapy, cloning, and the ability to modulate specific activities in the body may turn current modes of medicine upside-down. Many medical discoveries made today will presage medical cures to be made tomorrow. Yet, with all of these high-tech medical marvels at our disposal, down-to-earth basics such as manual manipulation and nutritional approaches presently remain among our best options for successful preventive medicine programs. Earlier this century, Thomas A. Edison predicted that "the doctor of the future will give no medicine, but will interest his patients in the care of the human frame, in diet, and in the cause and prevention of disease." In the years ahead, let us -- physicians and patients alike -- embrace Mr. Edison's prediction and look to natural sources for healing and wellness.

INTRODUCTION

BASIC FACTS ABOUT AMINO ACIDS

Amino acids are the building blocks of proteins. They are referred to as protein precursors, forming the polypeptide chains that are the basis of the protein structure. Amino acids are vital to the construct and integrity of every cell in the body: without them, our cells would first fail to hold their morphology (shape), and then fail to perform their unique metabolic functions. The amino acids can be classified into two major categories. The 8 essential amino acids are obtained solely from the diet, whereas the body can, under some circumstances, produce non-essential amino acids from other sources.

Essential Amino Acids	Non-essential Amino Acids
Isoleucine	Alanine
Leucine	Aspartate
Lysine	Asparagine
Methionine	Carnitine
Phenylalanine	Gamma amino-butyric acid (GABA)
Threonine	Glutamate
Tryptophan	Glutamine
Valine	Glycine
Conditionally Essential	Homocysteine
Cysteine	Hydroxylysine
Taurine	Hydroxyproline
Semi-Essential	Proline
Arginine	Serine
Histidine	Tyrosine

If the body does not obtain sufficient essential, conditionally essential and nutritionally semi-essential amino acids from the diet, then the body is said to be deficient. This deficiency may precipitate or predispose to illness or "dis-ease," as will be illustrated in many of the disorders outlined in this review. For those individuals with metabolic errors that impair their ability to metabolize or process specific amino acids, symptoms and sequelae of deficiency occurs. Oral supplementation of amino acids has proven to be generally safe and useful in certain disorders and in maintenance of optimal health.

A recurring theme in this review will be the concept of excitatory vs. inhibitory amino acids. This is a method of classifying these molecules according to their effect on cellular activity, particularly neurotransmission (the relaying of nerve signals) in the brain and nervous system. Taurine, alanine, GABA, and glycine are inhibitory amino acids. In other words, these four molecules function together to modulate chemical and metabolic processes. Aspartate, glutamate, and glutamine, among others, are excitatory. They are antagonistic to the functions of taurine, alanine, GABA and glycine.

WHY IS TAURINE VALUABLE TO THE BODY?

Taurine, chemical name 2-aminoethane sulfonic acid, is a conditionally essential nutrient. As such, taurine is derived directly from the breakdown of food but the body can produce its own taurine from other pre-proteins (the amino acids methionine and cysteine). Its role in the functions of the body has been long underestimated. Absence of taurine does not result in immediate deficiency and disease, but long-term deprivation can cause a multitude of health problems. Although popular as a dietary supplement in the Far East, Western medicine has only recently become aware of the diverse healing power of this nutrient.

Taurine regulates the most basic of cell functions -- genetic transcription (2). Maar, et al., demonstrated in mice that taurine acts as both an osmoregulator (to balance cell volume) and neuromodulator (protecting against over-excitation that may lead to cell death). Taurine plays these roles in human cells likewise, from head to toe.

Taurine is found abundantly in tissues that are excitable, rich in membranes, and that generate oxidants. Thus, it is the most prevalent of all the amino acids in the tissues comprising the skeletal and cardiac muscles and the brain. It is critical to the proper function of the brain, heart, lungs, and blood. Because it performs key functions in cholesterol metabolism related to bile acids, it is essential to the role of the liver, pancreas, and gall bladder. It also is key in the renal function of the kidney.

Taurine is essential for vision, directly to execute muscular motion and control, and indirectly to prevent disorders such as diabetes and cancer. It is absolutely indispensable in prenatal and infant development. We will review how taurine deficiencies can have serious medical implications during development, since it is nutritionally necessary throughout childhood.

Taurine is also the precursor to valuable analogs and derivative substances. Two of the newest applications for taurine are as acamprosate (calcium acetylhomotaurinate) -- now recognized as an effective treatment for alcoholism, and taurolin, an anti-infection, anti-microbial agent. This review will also explore several exciting novel uses for taurine currently under evaluation.

The average intake of taurine, via foods, varies widely, from 40 to 400 milligrams daily. Generally speaking, taurine is found in greater concentrations in animal products. The best food sources are:

Food Sources of Taurine (3)
Food	Amount	Taurine (mg)
Cheese	3 ounces	1000
Cheese, cottage	1 cup	1700
Granola	1 cup	650
Wild game	3 ounces	600
Pork	3 ounces	540
Oatmeal flakes	1 cup	500
Milk, whole	1 cup	400
Chocolate	1 cup	400
Yogurt	1 cup	400
Meat (luncheon)	1 cup	390
Wheat germ, toasted	1/4 cup	350
Egg	1 (medium size)	350
Turkey	3 ounces	240
Duck	3 ounces	240
Chicken	3 ounces	185
Sausage	3 ounces	185
Avocado	1/2 (medium)	75

Barring inborn errors of metabolism, oral supplementation replenishes decreased plasma taurine levels. Therapeutic dosing ranges from 1 to 3 grams daily, and should only be administrated with the advice of a qualified health care provider. In those individuals who develop stomach ulcers with aspirin, for instance, taurine is contraindicated.

Contemporary research now places taurine at the forefront of complementary and integrative medicine. While this article contains references to studies conducted on laboratory animals, it is the aspect of human nutrition that is our central focus. We will learn the value of this amino acid and the impact that deficiency can exert. By supplying our bodies with an ample quantity of taurine (or its precursors),by making smart dietary choices, by supplementing it orally, in the form of an injection or infusion, or introducing it via one of the newly discovered analogs or derivatives, we empower ourselves with a potent ally in the maintenance of good health.

HOW THE BODY GETS ITS TAURINE SUPPLY

Taurine is sometimes referred to as a beta-amino acid, referring to its deviation from the classic structure of an (alpha) amino acid. Taurine is unique from other amino acids in two other key ways:

1. It is not utilized in protein synthesis, but rather is found unbound or existing in simple peptide chains.

2. Its structure replaces the carboxylic acid element found in other amino acids with a sulfonic acid group.

[insert figure of taurine molecule]

The body synthesizes taurine from the amino acids methionine and cysteine. Vitamin B-6 (pyridoxal-5' phosphate) is a key cofactor in this process. Indeed, deficiency of B-6 will adversely affect the body's ability to manufacture and utilize taurine.

When cysteine was administered orally to a test group, production of taurine increased to reflect an 85% conversion to taurine. From cysteine, hypotaurine (an intermediary product in the metabolic process) is produced; its turnover into taurine occurs rapidly thereafter. Researchers have established that sulfur metabolism is conducted in a state of equilibrium such that the taurine form is a preferential form of end product.

Taurine synthesis is regulated by the enzyme cysteine sulfinic acid decarboxylase (CSAD). CSAD is activated under conditions that promote protein phosphorylation (a specific step in the conversion of amino acids into protein). Membrane changes initiated via glutamate or potassium promote CSAD activity, which implies an anti-excitotoxic role of taurine (see Excitotoxicity section).

As a conditionally essential amino acid, the body is able to synthesize taurine, but prefers to obtain supply directly from food sources. Consequently, intestinal health is a major factor in the ability to provide taurine in sufficient amounts for the multitude of biological processes in which it is involved. A study of mice found that, with age, the intestinal capacity to absorb taurine decreases (4).

[insert metabolic pathway for taurine synthesis]

Thus, taurine, which achieves good uptake via oral supplementation, may be the missing link in unlocking the secrets of many disorders we'll discuss in this review. Supplementation of the taurine precursors methionine and cysteine acts also as a source of hypotaurine, a preferred form of taurine in certain medical conditions. Clearly, the use of taurine supplements has been long overlooked for its potent therapeutic value.

CELLULAR TONICITY

Tonicity (synonymous with osmolarity) is a term that describes the status of cell fluid volume in relation to its external medium. Taurine has an important role in maintaining the delicate balance of tonicity in every cell in the body.

The osmoregulatory process involves several amino acids, one of the most critical of which is now identified as taurine. Cells demonstrate an ability to change their concentration of taurine in response to how plumped or shrunken in volume they become. Cellular volume changes in response to a range of insults, including infection, disease, and trauma; restoration of cell volume becomes essential to recovery from illness.

There are many ways in which the cells of mammals regulate their volume. To produce quick changes, cells either release or accumulate ions (such as sodium, potassium, and chloride) through ion-specific channel and transport systems across the cell membrane. For the long-term maintenance of intracellular volume, cells rely on organic osmolytes -- molecules that create intracellular osmolarity without adversely affecting cell function. Taurine, as an important amino acid osmolyte, helps to regulate osmolarity without causing additional perturbations of cellular tonicity. When cells are hypo-osmotic during hyponatremia, they would normally swell and could lyse if the hyponatremic state continued; taurine is thus extruded to help prevent such severe osmolar changes. In hypernatremia, cells are usually shrunken or "crenated" and have a reduced fluid volume; taurine uptake is thus increased to help regulate osmolarity and overt severe osmolar changes associated with possible cell death. This phenomenon was illustrated by Trachtman et al. (5), via induction of experimental hyponatremia in cats. Not only did cerebral taurine levels function in a significant linear relationship with intracellular water compartment size, but a similar effect was demonstrated in muscle. This work clearly indicates that taurine exerts a protective, osmoregulatory effect on cerebral and extra-cerebral tissues during extreme hyponatremia. A common pathway for the volume-dependent release of both ions and amino acids in the osmotic process has been identified. The concept of ion-dependent taurine concentration is key to understanding the ability of cells to recover from osmotic stress.

The cells of the nervous system have been studied in detail for their ability to modulate tonicity. The nervous system is comprised primarily of neurons (nerve cells), but also contains neuroglial (non-neuron) cells. The neuroglia not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular fluid, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and are able to release transmitters. Particular types of neuroglia are the astrocytes. Under hyperosmolar conditions, net taurine production increases in these cells so they may maintain high intracellular levels. When astrocytes swell, they take measures to release taurine in order to prevent irreversible damage from an extended state of osmotic imbalance. The pathway for taurine efflux also serves to conduct ions (potassium and chloride) from the cells as well. When researchers cultured astrocyte cells under hypo-osmolar conditions, the cells lost 88% of their taurine contents (in addition the amino acids alanine and aspartate) while restoring their normal volume (6). This study suggests that amino acid loss is a major factor in the process of volume regulation. In both astrocytes and neurons, metabolism of both hypotaurine and taurine is coupled to ensure delivery of taurine as it is needed to maintain osmolarity. Hence, it may be speculated that, just as proteins in the blood pull fluid out of the body tissues into the blood stream, taurine pulls fluid in or out of the cells, adjusting to conditions at the cellular level.

Mobility of cell membranes decreases following treatment with taurine unless calcium is co-administered. Thus taurine's biological effects occur most readily in the presence of calcium ions.

Cell volume is a repetitive theme that will appear throughout this review. Cell volume affects the most basic processes of cell function, and as such it exerts an important role in the onset, severity, and outcome of disease.

BRAIN

FREE RADICALS

Free radicals are highly reactive atoms that wreak havoc in the body by first converting otherwise stable molecules into unstable ones, thereby either producing another free radical in the process or causing them to bind with high affinity to the originating atom. These unstable free-radicals can oxidize molecules of healthy tissue, causing either cell death, mutagenic changes or an increase in unstable substrates such as oxidized LDL, which can readily stick to the lumen of arteries. Free radicals are particularly detrimental to brain tissue, which contains a high concentration of lipids (fat molecules) like LDL, which free radical atoms readily attack.

Physicians now regularly recommend the use of antioxidant vitamins (A, beta-carotene, C, and E) and the mineral selenium as countermeasures to free radicals. Recently, the value of taurine's precursor hypotaurine as a potent antioxidant has been discovered. If present in sufficient concentration where oxidation commonly occurs (like the brain), hypotaurine may protect against oxidative cellular damage (7). Remember that taurine's sulfonic acid group makes it a unique amino acid molecule; indeed, it is the sulfinyl group in the hypotaurine molecule which is responsible for its efficiency as a radical scavenger. The process by which hypotaurine proceeds to taurine has been shown to effectively scavenge free radicals.

Taurine is now being explored for its capacity to protect tissue against oxidative stress. In cerebellar neurons, stimulation by excitatory agents was effectively countered by taurine. While taurine did not directly decrease the levels of free radicals, it did increase cell viability. This may become an important alternate protective mechanism to offering protection against free radical damage.

SEIZURE/EPILEPSY

Seizures are the result of an electrical miscommunication between brain neurons. The onset of the seizure event is now correlated to significant changes in the levels of amino acids in the hippocampal region of the brain. Levels of the excitatory amino acids glutamate and aspartate, as well as the inhibitory amino acids GABA and taurine all increase during seizure. Additionally, the frequency and duration of seizure activity corresponds to notable increases of serine and glycine in addition to glutamate. A preemptive injection of taurine, glycine, or GABA elevates the threshold necessary to initiate seizure, thereby exerting a seizure prophylaxis (8).

Audiogenic epilepsy is a convulsive reaction to sound stimuli. By injecting taurine or GABA, or a combination, researchers were able to block the onset of seizure (9). They noted that potassium chloride (perhaps as the individual ions) countered the inhibitory effect of taurine and GABA. Recently discovered is the synergistic function that exists between taurine and magnesium, whereby the uptake of magnesium, a potential therapeutic agent in audiogenic seizures, is enhanced by taurine (10).

HYPOXIA and ISCHEMIA

Hypoxia is a condition where tissues fail to receive sufficient oxygenation. The central nervous system is least tolerant to hypoxic conditions. Symptoms, including change in mental status, confusion or encephalopathy, and coma or death ensue rapidly. Brain death usually occurs in three to five minutes in an anoxic state.

Glucose is one of the basic energy molecules that cells utilize to produce energy, with rapid death of neurons in the hypoglycemic state. A compromise in supplies of both oxygen and glucose results in the condition known as ischemia. Neurons and neuroglia (non-neuronal cells) swell rapidly, initiated by the rapid and large increases in extracellular levels of glutamate, aspartate, taurine, and GABA that are typical of excitotoxicity (see below).

Taurine has been shown to act as a preventive treatment against the disturbances associated with hypoxia. Taurine modulates the enzymes involved in energy metabolism in the brain, restoring adenine and ATP while reducing ADP and AMP levels. Through its ability to preserve the glutathione peroxidase system, recognized for its potent antioxidant capabilities, taurine protects cells from lipid peroxidation and deleterious membrane structure changes.

HEPATIC ENCEPHALOPATHY

Hepatic encephalopathy (HE) is a condition whereby the brain is poisoned by ammonia, a toxic by-product of metabolic and cellular reactions. It occurs in those with impaired liver function or liver damage, where the organ is no longer able to properly convert ammonia to urea for ultimate excretion via the urine. In addition, concentrations of amino acid precursors to urea that function as excitatory substances -- such as aspartate and glutamate (along with their metabolites glutamine and alanine) build up in the body, particularly in the striatal region of the brain. This may be caused by a reduced capacity of the astrocytes to transport the excitotoxins. Coincidentally, striatal taurine content is markedly lower, despite being transported at a greater rate across the blood-brain barrier. Taurine is redistributed to adjacent cells located in the central nervous system, apparently an attempt to protect those cells from damage. By its ready availability to CNS cells, taurine's role in cell volume regulation and neuro-protection may be particularly valuable in those suffering from HE (11).

EXCITOTOXICITY

Recall the Taurine and Tonicity section above, describing the role of taurine in cell volume. Excitotoxicity is the term for the presence of excess amounts of the excitatory amino acids, especially glutamate and aspartate, such that they create a toxic environment within cells (intracellularly) and among cells forming a unit of tissue or region of an organ (extracellularly), resulting in cell death. To combat this, cells release extra quantities of taurine, for its volume regulatory ability, thereby a buffering effect on dramatic changes in osmolarity. Taurine thus acts as both an osmoregulator and neuromodulator.

When neuronal and neuroglial impairments within the brain result from trauma (hypoxia, ischemia, contusion, or traumatic brain injury) or disease, excitotoxicity becomes a factor in the prognosis for recovery. In ischemia, glutamate and glycine are particularly elevated, with an accompanying release of taurine. The elevated levels are directly correlated to the degree of neurological damage. In viral meningitis, acute multiple sclerosis and myelopathy, glutamate and aspartate levels are doubled, with glutamate triggering a corresponding increase in taurine. In both trauma and disease, the role of taurine as a volume-regulating amino acid is key to combating excitotoxicity.

In the cerebral cortex, exposure to glutamate and aspartate causes intracellular swelling directly proportional to the increase in taurine. The release of taurine, prompted by the excitatory amino acids, is a function of the movement of ions and water across cell membrane that is mitigated by the excitotoxins. As with all cells, the release of amino acids in neurons of the brain is dependent on the presence of ions, which are responsible for opening and closing the membrane gates out of which the amino acid osmolytes flow. Calcium causes a release of taurine, GABA, aspartate, glutamate, glycine, and alanine in hypoxia, the proportions of which are guided by potassium-potentiated modifications to the cell membrane. Levels of taurine release are also modulated by the presence of both potassium and sodium ions. Ions regulate the release of taurine in the hypoxic or ischemic state, and an increased release of taurine may act to preserve neurons (12).

With encephalitis (inflammation of the brain), the concentration of glycine is significantly higher and taurine significantly lower than levels found in healthy people. Additionally, the amount of glutamate elevation is an indicator of the outcome for recovery. The neuronal damage incurred in encephalitis is a function of the excitotoxic neurotransmission that occurs with this condition.

SEVERE TRAUMATIC EVENTS

In people impaired by severe traumatic brain injury (TBI), elevated levels of the excitatory amino acid glutamate produces secondary brain damage including swelling of cells of the brain, called edema. Researchers have demonstrated a corresponding increase in taurine levels in this condition. The changes in the concentrations of both glutamate and taurine suggest that ongoing impairment to both neurons and neuroglia (non-neuron) cells results from severe trauma to the brain.

The body sometimes induces hypothermia when the brain suffers a contusion. In contusion, the levels of taurine, glycine, glutamate, aspartate, and glycine are elevated significantly; this occurs even more markedly with hypothermia. Post-trauma release of these amino acids occurs despite a reduction in blood flow in the brain. The alterations of osmolarity caused by the increase in amino acids, plus the self-induced state of hypothermia, serve as responses to protect the brain from further irreversible damage (13).

In people suffering from brain hemorrhage, their level of consciousness is inversely related to the total amino acid concentration in the brain. As with the research on hypoxia and ischemia, taurine functions as an osmoequivalent agent for correcting changes in cell volume.

Hyperammoniemia, either congenital or acquired, causes a number of neurological disorders. It may manifest as seizures (acute hyperammoniemia) or stupor/coma (chronic), though it most notably induces edema of the brain. It manifests as an oscillation between inhibitory and excitatory neurotransmission. When glutamine is elevated, causing acute excitotoxicity, taurine is reduced. When the neuroglia cells (astrocytes) increase their release of taurine, inhibitory neurotransmission is favored. If hyperammoniemia is compounded by a state of hyponatremia (lack of sodium) induced by hepatic encephalopathy, brain swelling worsens. This is accompanied by decrease in the levels of organic osmolytes including taurine.

BRAIN AGING

Taurine is found at consistently high concentrations in the brain, though levels decline with age. Researchers showed that the spatial learning ability of older rats was impaired, with the impairment correlated to the reduction in taurine in the striatum of the brain (14). Aged rats with modest reductions of taurine showed only modest reductions in learning. Additionally, striatal dopamine was markedly lower in aged learning-impaired rats, demonstrating a potential interaction between taurine and dopamine that may have implications for Parkinson's Disease (see below).

Alzheimer's Disease, the progressive and presently irreversible degradation of memory and loss of cognitive and learning abilities, may be traced, in part, to a decline in the vascular ability to generate nitric oxide. Vascular nitric oxide increases the open state of potassium ion channels, thereby protecting nerve cells from the excessive intake of calcium that is characterized by activity of beta-amyloid, the plaques speculated to cause neuronal damage. Generally accepted measures to promote vascular nitric oxide production include the supplementation of L-arginine, potassium, anti-oxidants and fish oil. The supplementation of anti-excitotoxic nutrients may also be valuable: taurine, along with magnesium, may target the channels of energy metabolism to reduce the risk of Alzheimer's (15).

Abnormal amino acid metabolic patterns characterize people with Alzheimer's Disease. In early stage Alzheimer's, blood levels of tryptophan and methionine -- the latter a precursor of taurine -- are markedly reduced. The ratio of plasma taurine to the products of the circulating levels of methionine and serine in the area also atypically increased. Researchers speculate that these abnormalities may contribute to the pathology of the changes in behavior and cognition that occur in Alzheimer's. In people with advanced Alzheimer's, cerebrospinal fluid (CSF) contains elevated concentrations of the excitatory amino acids glutamate and aspartate and decreased taurine level.

Researchers are not as far along in uncovering the relevance of amino acid profiles in Parkinson's Disease, a condition that affects countless older folks with a 'freezing' of their muscles, preventing normal motion from chewing and swallowing to walking and standing. In their CSF, people with Parkinson's have lower levels of eleven amino acids including taurine. Yet, their plasma levels of some of same amino acids were elevated. The calculated ratio of CSF to plasma amino acids is notably lower than that found in people without the disease, indicating that the transport of amino acids across the blood-brain barrier may be compromised in Parkinson's.

Parkinson's patients manufacture less dopamine, a neurotransmitter involved in a number of roles in cognitive function, compared to people unaffected by the disease. Taurine promotes dopamine release from the neuronal pool. The most dopamine is released in the presence of taurine's precursor, homotaurine. Where calcium is not present in the extracellular fluid, the brain still releases dopamine via taurine and homotaurine, whereas it cannot release dopamine via GABA without calcium. Researchers also note that increased levels of glutamate promote higher concentrations of taurine, GABA, and dopamine in the striatum of the brain. Perhaps the anti-excitotoxic role of inhibitory amino acids also promotes dopamine synthesis.

Taurine inhibits the firing ability of dopamine-stimulated neurons in the substantia nigra area of the brain by changing the conductance of chloride across the neuronal cell membranes. The ability of taurine to promote dopamine release and yet inhibit firing of dopamine neurons may provide valuable insight to the underlying etiology of Parkinson's Disease. Indeed, L-DOPA, a medication commonly prescribed to Parkinson's patients, not only boosts dopamine levels but alters the concentration of amino acids in the heart (where taurine is decreased), brain, and brainstem. Whether such alterations of the amino acid balance are beneficial or detrimental is yet to be determined.

In aging mice, researchers find that while hypoxia, hypoglycemia, and free radical exposure all enhance the release of taurine, the ischemic condition results in the greatest increase of taurine. This was particularly noticeable in the hippocampal region of the brain. While the presence of potassium in immature mice caused taurine release, this ion did not make a difference in adult and aged mice. However, in mice of all ages, taurine release was partially dependent on the presence on calcium. N-methyl-D-aspartate (NMDA), a glutamate agonist, participates with taurine release in a mechanism that is age-related: it has less effect on adult and aging hippocampi than in developing brain tissue. Taurine released during an excitotoxic state may constitute an important protective mechanism against neuronal death in the immature, developing, and aged brains (16-18).

Taurine promotes the activity of superoxide dismutase, a copper-containing protein enzyme that breaks down superoxide, a reactive free radical, into harmless oxygen and hydrogen peroxide. Researchers have shown that the activity of glutathione peroxidase, an antioxidant also involved in free radical binding, is notably higher in fetal brain cells exposed to taurine-rich media. Taurine also served to stabilize the fluidity of the membrane lipids, and as such, participates in postponing the aging process of brain neural cells.

THE HEART

During ischemia, hypoxia, and heart failure, the heart is subjected to a series of adverse changes. Taurine level is depleted in the failing heart. Taurine acts with a number of electrophysiological actions on cardiac cells by modulating the ion channels.

Calcium homeostasis is critical to stable myocardial contractile function. Taurine prolongs the action potential duration of calcium at high intracellular levels and shortens it at low levels. Changes in the intracellular taurine pool modulate calcium transport, and regardless of whether calcium is elevated or depressed, taurine exerts a cardioprotective action. Through the sodium-calcium transport exchanger in cardiomyocytes (heart cells), taurine permits the entry of sodium which favors a co-transport of calcium. It also modulates the activity of calcium channels to promote sodium influx. Within the area of the sarcoplasmic reticulum, changes in the intracellular taurine concentration modulate calcium transport by promoting calcium release and inhibiting an enzyme that triggers loss of calcium. In these regards, taurine has an essential function in ensuring stable calcium levels, which thereby promotes proper contractile function of the heart tissue. Likewise, potassium is also an important ion in heart cells. Taurine directly modulates the potassium ion current by increasing the current's action potential duration.

In ischemia, arrhythmia may be induced. Irregular heartbeat patterns are caused by abnormal extracellular calcium concentration in heart cells. With both low and high calcium, the number of beating cells, the beating rate, and the number of arrhythmic cells are adversely affected. In a research study, the addition of taurine attenuated this response of myocytes to varying calcium concentrations. Taurine's effect was quite specific, as analogs (including glycine) were not effective substitutes (20). The incidence of premature beats and tachycardia of the ventricles is notably decreased by taurine treatment.

Taurine is valuable in its role to protect the heart from oxidative stress and post-ischemic injury. It reduces lipo-peroxidation (free radical damage). In patients undergoing coronary artery bypasses who were pretreated with taurine, heart cell mitochondria (the cellular powerhouses) were subjected to far less extensive damage. The ability to scavenge free radicals is a potent cardioprotective role. When taurine is administered to people recovering from ischemia, the rate of the heart's action is notably different than non-treated counterparts. Both the quantity of lactate (a marker of ischemic challenge) and quantity of glutathione (a marker of oxidative stress) are attenuated with taurine. ATP levels (denoting cellular energy production) are also suppressed in ischemia. Through the modulation of lactate, glutathione, and ATP, taurine influences the ability and extent of recovery (21-22).

Thrombosis, the formation of a clot (thrombus) in the cardiovascular system, may result in myocardial infarction (heart attack). In this condition, serum endothelin concentration is markedly higher within the first several hours of onset. When taurine is administered with urokinase, a plasminogen activator (an enzyme that hydrolyzes arginine and lysine), serum endothelin levels decreased after eight hours post-infarction and stayed suppressed for several days. This suggests that taurine can beneficially affect serum endothelin levels and thus be a valuable adjunct to thrombolytic treatment (23).

Angiotensin is a hormone that the kidneys secrete to cause changes in blood pressure, either directly or by altering the sodium content of the blood. It is suspected that incorrect instructions from the angiotensin system are involved in producing hypertension. Researchers notice that in spontaneously hypertensive rats, minute amounts of angiotensin II cause increase in mean arterial pressure and heart rate, accompanied by increased release of glutamate (24). These changes were partially blocked by using an antagonist of glutamate -- taurine, glycine, or GABA. This research suggests that amino acid neurotransmitters may mediate, as well as contribute to, the cardiovascular effects of angiotensin.

Angiotensin II increases the rate of protein synthesis in heart cells. It also promotes a rise in intracellular calcium. In a particular type of heart cell (non-myocyte), angiotensin II promotes hyperplastic and hypertrophic growth, resulting in an increase in bulk. Taurine reduces the responsiveness of heart cells to these actions of angiotensin II, largely by altering calcium ion flux across cell membranes. It thereby may benefit cases of heart failure by suppressing undesirable cellular activities.

Angiotensin also activates the sodium-calcium transport exchanger, over which taurine exerts control. Taurine depletion causes an impairment of myocardial relaxation; angiotensin counters this effect. Taurine deficit adversely affects heart contractile ability and ion transport, effects that are ameliorated by angiotensin II.

Taurine lowers arterial pressure by promoting diuresis and vasodilation (opening of the vessels). A depletion of taurine in the heart leads to a decrease of plasma atrial naturetic peptide (ANP) in the vascular system, causing additional alteration of arterial pressure. ANP secretion caused by increased blood sodium levels is depressed by taurine depletion, leading to a state of diuretic imbalance: excess salt in the absence of taurine leads to an increase of arterial pressure.

Taurine makes up nearly 50% of the free amino acids in the heart cells. It has a dramatic effect on the success of recovery from life-threatening cardiac conditions. Researchers conducted a six-week comparative study of oral supplementation of taurine versus Coenzyme Q-10 in patients with congestive heart failure attributed to cardiomyopathy (including ischemia) and exhibiting a grossly compromised ejection fraction (the ability of the heart to pump blood) (25). The results were surprising: the taurine-treated group exhibited significant treatment effect on systolic left ventricular function, with no observable effect in the Co Q-10 group. Additionally, its role in blood pressure, caused by its interaction with substances that modulate diuresis, attests to taurine deficiency as a major factor in the hypertensive state.

When treated with taurine, an increase in survival rate and reduction of elevated calcium content in aortic and myocardial tissue is found in mice, which suggests that taurine's regulation of calcium flux may prevent the progression of arteriosclerosis (26). Additionally, taurine's modulation of calcium yields a stabilizing action on systemic arterial pressure and prevents arrhythmia or ectopy in the hypertensive heart.

BLOOD, BILE AND CHOLESTEROL

THE LIVER

The liver is the largest solid organ in the body. It is composed of 100,000 lobules, which in turn are made up of specific cells called hepatocytes. Nearly two quarts of blood flows through the liver each minute, so this organ is continually involved in the processing of blood, acting to:

help with the absorption of nutrients from food
synthesize blood proteins (albumin)
destroy old red blood cells for reuse of some of the component molecules
convert wastes for excretion by kidneys

The liver is a primary site for metabolic processes. It processes most of the food we ingest and enables nutrients to become available to cells in a readily usable form. A network of minute tubules in the liver collects bile. Bile is a mixture of salts, bilirubin (a product from the breakdown of red blood cells by the liver), cholesterol, and fatty acids. The liver sends collected bile to the gall bladder for storage. When food enters the stomach and proceeds to the duodenum (the first part of the intestinal area), cholecystokinin, a hormone, triggers the gall bladder to release bile for use at the duodenum. Here, along with lipase (enzymes of the pancreas) and contractions of the intestinal muscle, bile acts to:

emulsify (break down) fat into minute particles so digestive enzymes can process it
promote the absorption of lipids by binding to fat-soluble vitamins (A, D, E, and K), along with essential fatty acids, to permit their absorption into the lymphatic system.

By this complete and efficient cycle, the vast majority (over 90%) of bile salts are reclaimed by the liver for reuse.

The liver serves as a primary detoxification site, filtering out impurities in the blood. It removes chemical, bacterial, and allergic substances before they can irritate the body. When digested food molecules proceed from the intestine to the liver, it checks, and even may alter, the concentration or chemical nature before making them available to the body.

BILE

The liver detoxifies and prevents the introduction of substances damaging to the body. These functions are carried out only if the liver is not impaired or damaged, and only if bile is produced and made available in an uncompromised fashion. Taurine conjugates (couples) bile acids into cholagogues (agents that promote the flow of bile into the intestine) and cholerectics (substances that stimulate the liver to increase production of bile), resulting in the following forms of bile salts:

Taurocholic acid (taurocholate) (TC): is formed when cholic acid and taurine conjugate. The sodium salt of taurocholic acid is the chief ingredient of the bile of all meat-eating mammals, man included.
Taurodeoxycholic acid (TDC): a bile salt formed in the liver by the conjugation of deoxycholate with taurine.
Taurolithocholic acid (TLC): a bile salt formed in the liver from lithocholic acid conjugation with taurine.
Taurochenodeoxycholic acid (TCDC): a bile salt formed when chenodeoxycholate conjugates with taurine.

The liver has the unique feature of a dual blood supply. In a study of rats, researchers found that taurocholate (TC) permits bilirubin excretion to become bilary product at a rate of 90% (27). Without this taurine conjugate, bilirubin excretion drops by one-third, with the majority of the excretion failing to proceed to the intestinal tract as intended. TC is critical for ensuring the correct directional transport of bilirubin to serve as bile, rather than spilling undesirably into the blood flow to other parts of the body.

In conditions where TC is not present, bile salts can exert a detrimental effect on the body. Bile salts can precipitate to initiate gallstone formation. Bile salts can be classified into two categories: hydrophilic (attracted to water) or hydrophobic (dispelled by water). The balance between hydrophilic and hydrophobic bile salt mixtures may significantly affect the early stages of gallstone formation.

TC and tauroursodeoxycholate (TUDC) are hydrophilic. They inhibit the precipitation of cholesterol by promoting a stable liquid-crystal formation. When hydrophobic bile salts such as taurodeoxycholic acid (TDC) or taurochenodeoxycholic acid replaces TC and TUDC, cholesterol crystallization occurs. Bile salt hydrophobicity influences the shape and extent of cholesterol crystallization. Recently, another taurine conjugate has been identified and noted for its hydrophilic properties.

Taurohyodeoxycholic acid stimulates greater cholesterol secretion than TUDC and does not have hepatotoxic effects (28). While one might call TC and TUDC the good guy biles, don't be quick to judge TDC and TCDC as bad biles. Hydrophobic bile acids may enhance lipid peroxidation, thus imparting valuable free-radical scavenging activities. So it is clearly demonstrated that taurine engages bile products that are not only integral to liver function, but essential for general health.

In addition to its role in bile salts, taurine has considerable importance in cellular maintenance functions in the cells of the liver. As with the neurons and neuroglia of the brain, taurine exerts cyto-protective effects when hepatocytes are exposed to hypoxia with the presence of calcium ions. When conjugated with bile acids, taurine increases membrane mobility as well as fluidity. Without proper levels of taurine, the liver cells would be susceptible to osmotic changes and their membranes would become less permeable. The resulting impairment to the liver would significantly compromise its ability to purify the blood, allowing toxins to spill into the body.

Taurine and glycine exist in the presence of a time- and dose-dependent exchange mechanism. After administering glycine to rats, researchers discovered that it produced a notable suppression of hepatic taurine content in the liver. Yet, this taurine decrease was not found in other taurine-rich organs such as the brain, heart or kidney. The mechanism for hepatic concentration of these two amino acids serves to alter liver concentrations of these amino acids without adversely affecting the rest of the body (29-30).

CHOLESTEROL

In the blood, cholesterol is carried in two forms: low density lipoproteins (LDL) and high density lipoproteins (HDL). Elevated LDLs are implicated in a range of heart and vascular diseases, including myocardial infarction (heart attack) and arteriosclerosis (clogging of the arteries). HDLs are recognized for their protective function on both the heart and vasculature. Recently, physicians have adopted 2:1 as the ideal ratio of total cholesterol to HDL. Taurine can attenuate increases in total and LDL cholesterol in people consuming a high fat, high cholesterol diet (31). It might help some people to reach that magical lipids ratio.

Dietary taurine supplementation is shown to benefit situations where body cholesterol status is high as well as normal. Rats fed a high cholesterol diet plus high doses of taurine demonstrated significant reductions in plasma levels of total cholesterol (32% reduction), LDL ("bad") cholesterol (37% reduction), and triglycerides (43% reduction) when compared to rats fed a high cholesterol diet without extra taurine. In rats fed a high taurine diet versus a cholesterol-free diet, those with the extra taurine showed marked decrease in plasma total cholesterol, LDL-cholesterol and triglycerides. The taurine supplementation to the cholesterol-free diet also produced reductions in hepatic triglycerides (43% reduction) and elevated free fatty acids in the liver (77% increase) (32).

Taurine conjugates of all bile acids suppress very low density lipoprotein (VLDL) secretion. VLDLs are produced through a series of reactions of protein with aldehydes. Researchers have demonstrated that taurine exhibits a high reactivity with aldehydes, thus it acts to inhibit protein modification to LDL. TC, TUDC, and even TDC exert a dose-dependent suppressive action on the secretion of VLDLs.

With regard to HDLs, taurine enhances serum HDL concentration in a dose-dependent manner. High fat diets produce hypercholesterolemia (elevated cholesterol), atherosclerosis, and accumulation of lipids on the aortic valve of the heart. In mice, taurine treatment lowers serum LDL and VLDL by 44% while elevating HDL by 25% (33). Taurine also decreases the presence of cholesterol in the liver by 19%. The cholesterol-lowering action of taurine may lie in its ability to promote the conversion of potentially detrimental cholesterol to relatively harmless bile acids.

Tauroursodeoxyycholate (TUDC) acts as a hepatoprotective bile acid, not only countering the cholestatic effect of taurolithocholate (TLC) that induces a decrease or cessation of the flow of bile, but reverses the process as well. The taurine precursor methionine, in the form of S-adenosyl methionine (SAMe), acts in a synergistic way with TUDC to moderate cholestasis resulting from promotion by TLC. By increasing calcium content in the liver and serum calcium concentration and by enhancing bilary calcium concentration, taurine ameliorates ischemic damage of the liver (34).

From all of these research discoveries relating to the ability of taurine to conjugate bile acids and thereby promote fat absorption, a new drug to treat cholestasis has been synthesized. Sodium tauroursodeoxycholate has a beneficial effect on cholestasis, lowering the characteristic elevations of serum cholesterol, bilirubin, and bile acid levels. The role of taurine as a potent lipid metabolizer cannot be overlooked or underestimated. Its value as a therapeutic agent against the deleterious effects of cholesterol is just becoming understood.

Just recently, researchers have discovered gender-based differences in the ability of the liver to transport ions and osmolytes. In studying rats, it was found that the uptake of the organic ions is greater in females, whereas males were more effective with osmolytes (35). Female rats had decreased expression of the osmolytic peptide and transcription process necessary for osmolyte transport. They also exhibited decreased membrane lipid fluidity. This study demonstrates a decreased sodium-dependent bile salt uptake in the liver cells of the female rats. This potential difference between liver function in males and females warrants further study.

CHOLESTATIC LIVER DISEASES

CIRRHOSIS:

Cirrhosis produces scarring of the liver, particularly at the bile ducts. When ducts become inflamed and occluded, the liver tries to compensate by forming new bile channels. This process results in unplanned overgrowth of tissue as well as scar tissue formation. Cirrhosis thus places the entire cycle of bile production, release, action, and re-uptake at risk. One of the most common causes of cirrhosis is alcoholism. The chronic consumption of alcoholic beverages puts a formidable burden on the detoxifying ability of the liver. Hydrophilic bile acids -- particularly TUDC -- protect proteins and lipids from oxidative damage due to alcohol. Taurine, as the conjugate of this bile acid, thus plays an integral role in protection against the cytotoxic damage of alcohol.

While the liver puts forth a valiant effort to prevent the cellular destruction that alcohol consumption produces, it may win the battle but not the war. When alcohol finally wears the liver down, the permanent damage of cirrhosis sets in. The hydrophobic bile acid TDC has metabolic properties that may lead to its utility as a therapeutic agent for the treatment of cirrhosis and other chronic cholestatic liver diseases. When TDC was administered to a group of people experiencing primary bilary cirrhosis, their serum liver enzymes showed improvement. TDC was better absorbed than the current treatment of choice -- unconjugated ursodeoxycholic acid. The treatment was well tolerated and without reported side effects (36).

HEPATITIS:

Hepatitis is a set of conditions, labeled Hepatitis A, B, C, and D, that exist in either a chronic persistent or chronic acute state. TUDC has more beneficial biochemical and metabolic properties than its unconjugated form, ursodeoxycholic acid, in patients with hepatitis. Over a six month period, researchers found that a group of TUDC-treated patients demonstrated a progressive improvement in the biochemical expression of chronic hepatitis.

CELL DEATH:

In severe cholestatic diseases, hydrophobic bile-induced injury is due to cytolysis, in which the cell dissolves. In more moderate cases of cholestasis, apoptosis (cellular deletion characterized by fragmentation and subsequent ingestion by other cells) is the main mechanism by which bile acid toxicity is expressed. For the range of cholestatic diseases, however, the degree of irreversible, permanent damage to hepatocytes is dependent on the liver’s ability to detoxify hydrophobic bile acids. TUDC is able to reduce both cytolysis and apoptosis, exerting a direct hepatoprotective effect against hydrophobic bile acids that initiate or promote cell death.

Taurine itself may also have a role in the prevention of hepatocyte apoptosis and necrosis. Taurine acts directly as an antioxidant on the free radical intermediates. On a genetic transcription level, taurine mediates nitric oxide inhibition through its effect on mRNA. Taken together, these two mechanisms indicate a potential therapeutic role for taurine in hepatocyte injury.

OCCUPATIONAL OR ENVIRONMENTAL EXPOSURES TO SOLVENTS:

Dangerous exposure to solvents is common hazard for industrial workers in chemical and petroleum refinement, the plastics, the automotive industries, and the dry cleaning industry, among many others. Yet, we all are exposed in less conspicuous ways: the most insipid results from outgassing, the slow yet continual dissipation of solvents from new carpeting, furniture, automobiles, and house paints. Solvents have been linked to birth defects, sterilization, headache, chronic fatigue, arthritic-like inflammation, and a number of additional medical ailments.

Solvents have a notably deleterious effect on the function of the liver. Toluene, a solvent derivative of coal tar that is used in dyes, explosives, and as an agent in the extraction process of substances from plants, causes a rise in total serum bile acids and an elevation in the activity of liver enzymes. Accumulation of TC is significantly inhibited. Toluene inhibits the transport and accumulation of bile acids by hepatocytes in a damaging fashion. Similarly, xylene, a solvent chemically related to toluene, interferes with the rate of uptake of TC. While the effect was reversible if sufficient time was permitted, exposed individuals rarely have the opportunity to knowingly make such a conscious effort.

Carbon tetrachloride, a substance long used in the dry cleaning industry but now being abandoned in favor of more 'friendly' solvents, adversely affects liver function. In a lab study that produced degenerated hepatocytes and necrosis damage from exposure to carbon tetrachloride, researchers discovered that the concurrent administration of taurine with carbon tetrachloride could ameliorate the damage. Taurine moderated the extent and severity of lesions and reduced the number of cancer-antigen positive hepatocytes. Important to counteract the hepatocyte degeneration, lesions, and necrosis characteristic of carbon tetrachloride exposure, taurine also served to protect against DNA damage.

THE KIDNEY

Taurine is essential to the proper function of the kidney. Without it, renal capacity is diminished such that the process of excretion of unwanted substances from the blood is grossly impaired. Ordinarily we are each born with 2 kidneys, comprised of about one million functional units known as nephrons. Every drop of plasma passes through the kidneys in order to be purified. During this continual process of diuresis, the kidneys adjust the content of the plasma by removing fluid, electrolytes and urea as needed.

People with chronic renal failure have elevated levels of urea in the blood, a condition called uremia. They also exhibit markedly low levels of taurine despite an adequate or elevated concentration of precursor amino acids such as cysteine and methionine. An impaired ability to metabolize the precursors to taurine may exacerbate taurine depletion. Left uncorrected, low taurine levels, combined with elevated homocysteine (an undesirable by-product of cysteine metabolism), causes an increased incidence of cardiovascular disease in uremic patients.

Taurine acts in the kidney, as we've seen with other organs, as an organic osmolyte. Depending on the tonicity (concentration) of the final urine emerging from the kidney, the medulla area will deliberately modify its own tonicity. When the fluid in medulla is hypertonic (more concentrated), its cells accumulate taurine and similar osmolytes, thus exerting a conservatory effect upon taurine. This osmotic response results from an increased activity of specific sodium-coupled transporters. Thus, the kidney exercises self-preservation by modulating the volume of its cells to promote its functions. Trachtman et al, (37) demonstrated the therapeutic and preventative effects of taurine in diabetic rats. Taurine administration reduced the total proteinuria and albuminuria by approximately 50%, prevented glomerular hypertrophy, diminished glomerulosclerosis and tubulointerstitial fibrosis, overall ameliorating diabetic nephropathy by reducing renal oxidant injury.

VISION

In the healthy eye, taurine is found in very high concentration. Lens transparency is a function of the amino acid pools available in the lens. Lenses subjected to oxidative stress exhibit characteristic changes in their amino acid profile, with taurine levels greatly depressed. This direct effect of oxidation subsequently causes both short-term and permanent changes in lens transparency.

A cataract is a clouding of the normally clear lens of the eye. It impairs vision, though today visual loss is often reversible by surgical measures. Cataract formation is speculated to be due largely to oxidation of protein and glycosylation of proteins in the lens of the eye. A lack of the antioxidant nutrients (taurine, Vitamin A, carotenoids, Vitamin C, and Vitamin E) is major factors for the development of cataracts. Taurine acts as an antioxidant by preventing changes in the levels of glutathione (a selenium-requiring substance), ATP, and insoluble proteins -- factors that predispose the formation of cataracts. It also prevents oxidative damage by scavenging hydroxyl radicals. Through a reaction with a sugar-based molecule, taurine and hypotaurine reduce the glycation and denaturation of lens protein (38).

Taurine plays a critical role in the structure and function of the photoreceptors (rods), responsible for the ability to see in both low illumination and night conditions. Mechanisms that both permit its efficient uptake and prevent its depletion are critical. Through its osmoregulatory function, taurine is responsible for making the rod outer segment of the retina resistant to injury that would otherwise be sustained through osmotic changes. By doing so, it assists with the regenerative process of rod cells and protects the rod outer segment against osmotic, mechanical, and light-induced damage. A high-affinity, taurine-specific uptake system is present in the rod outer segment system. Through modulation of membrane ion channels, taurine increases calcium uptake to promote the transmission of visual signals from the retina to the brain.

Taurine is important for the regeneration of damaged cells in the retina. It functions to phosphorylate specific proteins and increase cellular outgrowth. The promotional effect of taurine in cellular regeneration is compromised in the presence of drugs that cause the activation of the enzyme protein kinase C or phosphatase inhibitors. Researchers are observing that Tamoxifen, a drug recently approved to fight breast cancer and prevent new tumors, exerts a negative action on retinal levels of taurine by acting on the phosphorylative process (39). Whether long-term administration of drugs with this type of depressive effect on taurine has a deleterious effect on vision requires further study.

Retinal dystrophy, an age-related degenerative disease, affects the pigmented epithelium and photoreceptors of the retina. The disease may be caused by disturbances in the metabolism of melatonin, a hormone produced in the pea-sized pineal gland of the brain and associated with the regulation of the sleep-wake cycle. Taurine administered in concentrations that equal the level of melatonin normally present blocks the action of melatonin (40).

Retinitis pigmentosa (RP), characterized by visual field loss and night blindness, is thought to be a hereditary disease but it also affects people without genetic predisposition. It is marked by the degeneration of the retina of both eyes, beginning with the rods, which leads to tunnel vision and, eventually, to legal blindness. Nutritional factors are now recognized as important factors in the reversal of retinitis pigmentosa. Allen et al (41) were able to help two RP patients recover their visual capacities, using nutrients including taurine. Allen's use of taurine was based on an important finding by Hayes et al (42), which indicated that the absence of intestinal bacteria, which normally causes the kidneys to excrete taurine for use by other parts of the body such as the eye, leads to a sometimes erroneous presumption that RP is inherited and consequently not treatable. In a study using rats, abnormal patterns of uptake of the excitatory amino acids glutamate, glutamine, and aspartate, as well as GABA and arginine, were noted prior to photoreceptor degeneration (43). During degeneration, taurine and glycine uptakes are affected. After degeneration was established, the altered patterns of amino acid uptake continue, with specific areas of retinal cells affected in various ways. This suggests that amino acid neurochemistry may have an underlying metabolic role in the onset and progress of retinitis pigmentosa.

Taurine and zinc interact to influence the development of the retinal structure and function in the eye. Both nutrients promote the healthy oscillatory potentials necessary for vision, whereas deficiency of either taurine or zinc depresses the strength of specific potentials. The depression of oscillatory potentials greatly compromises photoreceptors and can lead to retinal dysplasia.

Deficiency of taurine has been identified as the cause of a recent two-year epidemic of optic neuritis diagnosed in Cuba (44). Ranging from debilitating medical conditions to this transient bout, taurine is well established in its multiplicity of roles in the eye.

GASTROENTEROLOGY

Inflammatory bowel disease is a chronic condition characterized by diarrhea, low-grade fever, fatigue, weight loss, and abdominal cramps. Joint pain and skin lesions can result from accompanying malabsorption. It is frequently associated with colon ulceration and/or inflammation, which cause an increase in colon weight -- a reflection of tissue edema. Treatment with taurine reverses the discomfort, added colon weight, and bouts of diarrhea. It is speculated that taurine ameliorates IBD by increasing the ability of the colon to defend against oxidative damage (45).

In some people, pain relievers classified as non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, can cause gastric ulceration. Taurine exerts a protective effect on this GI insult through its antioxidant properties. By inhibiting neutrophil (white blood cell) activation and lipid peroxidation, taurine is able to prevent the adhesion of neutrophils to the gastric lining (46).

Inflammation in the small intestine may be caused by a number of factors, including bacterial overgrowth, food contamination, and high levels of bile acids. This condition is marked by loss in body weight due to reduction of food intake, increased intestinal inflammation, and shortened length of the small intestine. Taurochenodeoxycholic acid (TCDCA) is able to normalize these manifestations, prevent increases in the hydrophobicity of the bile (to counter additional damage), and attenuate the intestinal inflammation (47). It should be considered as an adjunct treatment to primary therapy, depending on the cause of the inflammation.

PULMONARY FUNCTION

The depletion of taurine is particularly harmful to pulmonary tissue. Alveolar macrophages reside on the surface of lung alveoli. Their main purpose is to ingest inhaled particular matter to dispose of it. However, alveolar macrophages become more susceptible to reactive forms of oxygen when deprived of the antioxidant protective capacity that taurine provides.

Taurine possesses particular beneficial activities in people afflicted with cystic fibrosis (CF). CF is an inherited condition that affects the respiratory and digestive systems. Patients are notorious for producing thick mucous, which clogs instead of lubricates the pulmonary system. CF patients often experience steatorrhea (fatty stools), indicative of an inability of their GI system to process and absorb dietary fat properly. The first of its roles in CF, taurine is suspected to act to improve the process of fat digestion. In children with CF and steatorrhea, taurine supplementation resulted in a decrease of both fecal fatty acid and total sterol excretions (48). Taurine supplementation can provide a more healthy profile of triglyceride absorption and fatty acid composition of chylomicrons. As a result, taurine is useful as an adjunct therapy for the management of CF patients experiencing complications of fat malabsorption and essential fatty acid deficiency (49).

CF is also marked by liver disease, a complication that is often a cause of death. We have already reviewed the role of taurine in liver function. In a year-long study of CF patients with poor liver function, treatment with taurine provided a notable increase in serum pre-albumin and a trend toward the reduction in fat malabsorption, with no severe side effects. Thus, taurine's second role in CF is its action in bile synthesis. This finding, plus the ability to correct GI absorption, makes taurine a novel and valuable aid for CF treatment (50).

Bioavailability of Vitamin E for cellular uses is a problem in CF patients. A pancreatic insufficiency and an adverse bile acid conjugation that results from an abnormal glycine/taurine ratio of bile acids likely cause this situation. Consequently, serum Vitamin E is notoriously low in CF. Taurine's third role in CF is in the promotion of vitamin E absorption, by reducing the glycine/taurine ration of bile acids in the duodenal juice of CF patients, thereby providing an intestinal environment conducive to the uptake of Vitamin E.

Lung fibrosis may result from a number of factors. It may occur from the use of the anti-arrhythmic drug amiodarone, which induces elevated lung hydroxyproline (a marker of fibrosis -- collagen accumulation) as well as lung phospholipids (a marker of phospholipidosis). Treatment with taurine causes a significant decrease in both of these deleterious consequences and thus may be an important option for the prevention of the adverse side effects of amiodarone use (51).

Fibrosis may also result from toxic chemical exposure. There are numerous facets to toxin-induced damage to lung cells and tissue that have been studied in animal models of induced interstitial pulmonary fibrosis. First, taurine or niacin alone, with the combination of taurine plus niacin yielding the most beneficial results, can reverse increased lung lipid peroxidation. All three approaches decrease the accumulation of collagen in the lung, as well as phospholipid activity. Second, the ability to scavenge free radical reactive oxygen molecules and to stabilize cell membranes also contributes to taurine's action to suppress lung collagen accumulation and oxidative stress damage. Finally, both taurine and niacin are able to down-regulate genetic actions that express lung fibrosis. Taurine and/or niacin can completely or partially, ameliorate pulmonary fibrosis of a chemical origin (52-54).

Radiation exposure may also cause lung fibrosis. Taurine, in its cytoprotective role, is able to resist the action of free radical damage that would otherwise be caused by radioactive substances. Its suppression of transcription counters the production of collagen and elevations of hydroxyproline in pulmonary tissue, serving to protect against radiation pulmonary injury (55).

Silica-induced lung injury is an occupational hazard of industries such as mining, sandblasting, metal grinding, and ceramic manufacturing. Hypotaurine, a taurine precursor derived from cysteine, is able to significantly inhibit silica-induced lipid peroxidation (56). This antioxidant effect is also noted in the prevention of damage from acute ozone exposure, especially in the bronchioles. Alterations in the epithelial cell junctions in the airway are usually seen as both an immediate and delayed effect of ozone. In animals pretreated with taurine prior to exposure, these changes occurred only during the immediate period of time following exposure. Additionally, fibril effects (decreased number and breaks in strands) are prevented with the taurine pretreatment. While injury induced by ozone is transient, taurine can exert a protective effect against both immediate and delayed oxidant injuries (57).

Finally, taurine also modulates lung endothelial cell damage. It significantly attenuates apoptosis due to oxidative stress. Endothelial cell necrosis is halted with similar efficacy. These functions are due in large part to the antioxidant activity and regulation of intracellular calcium flux. This has great implications for the therapeutic value of taurine in inflammatory-type lung conditions (58).

HEMATOLOGY

Taurine is of particular value to the preservation of erythrocytes (blood cells). Researchers have found that it is able to effectively suppress hemolysis (bursting) due to osmotic imbalance. It interacts with the membranes of blood cells to protect against free radicals. Taurine acts as both an antioxidizing agent and a membrane stabilizer to maintain the functions of membrane-bound protein enzymes. New studies show that erythrocytes deliberately release taurine when ionic changes compromise cellular osmolarity.

NEUROMUSCULAR DISORDERS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the progressive degeneration of nerve cells in the brain and spinal cord that control voluntary muscle movement. After the nerve cells shrink and disappear (without any preceding abnormalities), the muscle tissue wastes away because of the lack of nerve stimulation. Transport of glutamate is disturbed in these patients, for whom researchers have recently identified an elevation of taurine levels. The increased taurine, as the final product of the sulfur amino acid metabolic pathway, suggests that cell death in ALS patients may be a result of undesirable increases in the levels of excitatory sulfur amino acids that counter the ability to transport and uptake cystine and/or glutamate (59-60). Additionally, it has been reported that the sulfur amino acid metabolic process is impaired when there is inadequate folate or impairment of the folate cycle. Vitamin B-6 is a cofactor in many biochemical reactions involving nitrogen metabolism. A deficiency alters concentrations of multiple amino acids in tissues. While taurine may not act as a therapeutic agent for ALS, the measurement of elevated taurine has provided a clue into the puzzling etiology of ALS.

INFLAMMATORY AND DERMATOLOGICAL DISORDERS

In inflammatory disease, plasma taurine becomes depleted, signifying a greater demand by the body in this state. Taurine prevents the tissue damage that may otherwise result from inflammation. The mechanism involves taurine monochloramine, a product formed through a series of reactions based in the leukocytes (white blood cells) which chlorinate the taurine molecule. In a dose-dependent manner, taurine monochloramine inhibits the production of substances that promote inflammation, such as nitric oxide, prostaglandin PGE2, and tumor necrosis factor. Thus, taurine itself counters the inflammatory response by reducing the expression of nitric oxide synthase and cyclooxygenase-2 (COX-2), not unlike the role of the new COX-2 specific inhibitor drugs celecoxib and rofecoxib. Taurine monochloramine reduces the toxicity of free radical oxidants, serving to decrease the production of tissue-damaging inflammatory substances and regulate the function of neutrophils to promote their protective effect. Taurine also works cooperatively with the cysteine pool to lessen the depressive impact of tumor necrosis factor on cells of the lung.

The taurine derivative N-chlorotaurine is a weak oxidant produced by leukocytes in response to bacterial and fungal exposures. Recently, researchers have also found that it destroys pathogens incurred as a result of inflammatory reactions (62). This may become an important addition to the list of substances that are useful as antiviral agents.

The neutrophil-based anti-inflammatory effect of taurine is important in dermatological conditions. Psoriasis is essentially a skin disorder in which hyperproliferation occurs. Psoriasis of a chronic, plaque-type nature has been correlated to marked depression of neutrophil taurine levels (63). As odd as it may sound, bile acids, produced by the liver, are involved in the activity of keratinocytes, cells of the living epidermis which produce keratin in the process of differentiating into dead or fully keratinized cells. Researchers have demonstrated that the taurine conjugated bile acid TUDC exerts a growth suppressive effect on keratinocytes, and thus its presence may be of importance in skin conditions (64).

DIABETES

In both forms of diabetes -- insulin dependent (Type 1) and non-insulin dependent (Type 2), taurine exerts a multitude of beneficial actions. Its lack or decrease of availability is a major factor in the production of symptoms and complications of these illnesses.

Platelet aggregation in Type 1 diabetes results in an increased risk of cardiovascular incidents. When taurine is supplemented, these patients show an increase in both plasma and platelet taurine levels that raise the threshold at which aggregation can be triggered. This action is specific to diabetics -- researchers did not find a similar response in healthy subjects (65).

Taurine changes the adverse blood lipid profile that is associated with the diabetic condition. Researchers found that elevated plasma triglycerides and LDL cholesterol in diabetics were countered through administration of taurine. However, researchers point out that taurine supplementation altered the lipid profile only after the diabetic state was induced. Through its lipid peroxidative function, taurine is able to decrease adverse lipid profiles in diabetics. The time and dose of taurine are variables that require further study (66). Additional research also indicates that chronic administration of taurine is able to reverse increased serum levels of LDL with no adverse effect on serum glucose levels. This effect is largely due to a correction of vascular endothelial vasodilation characteristic of the diabetic state (67).

In Type 2 diabetics, the impaired glycemic control is largely due to peripheral insulin resistance, hepatic insulin resistance, and a failure of beta cell function. New complementary therapies including dietary changes, exercise programs, and weight loss often can produce improvement in peripheral insulin resistance. It can also be treated with chromium, vitamin E, magnesium, and soluble fiber. Recently, taurine has found a role as well, correcting the metabolic anomalies in vascular smooth muscle produced by Type 2 diabetes. So taurine, as well as the more established natural agents for Type 2 diabetes, may reduce the risk of vascular impairment. Recognizing that these approaches may be adequate but not optimal measures, they are worthy of consideration as adjuncts to drug therapies (68).

In models of diabetic mice, researchers found that taurine supplementation yields specific beneficial effects on levels of malondialdehyde (MDA), a marker of lipid peroxidation resulting from free radical damage. In Type 1 diabetes, levels of MDA in the liver and islets are particularly elevated; taurine is able to counteract this abnormal elevation. It is of interest is that MDA levels in Type 2 diabetic mice could not be altered by taurine. While taurine did not alter the activity of glutathione peroxidase in the Type 1 group, taurine did exert a promotional effect on the its levels in the islets of the type 2 animals. These results indicate a protective effect of taurine against lipid peroxide formation (69).

Diabetes is notable for its impact on eyesight. Diabetes induced in rats produces a generalized decline in the content of free amino acids in the retina and retinal pigment epithelium of the eye. This suggests a deleterious action of diabetes on amino acid transport systems, which results in alteration of the cellular amino acid balance. Dietary supplementation of taurine is able to correct abnormal elevations of MDA and thus to prevent depletion of glutathione, and to decrease glucose and ATP utilization. While taurine supplementation may not necessarily be as effective as other methods of correcting the antioxidative imbalances that produce diabetic cataracts, it may serve as an adjunct to other treatment measures (70).

Another complication of diabetes is diabetic nephropathy, where the kidneys fail to regulate the excretion of protein via the urine. It is the leading cause of end-stage renal disease and occurs in over half of Type 1 diabetics. Diabetic nephropathy causes proteinuria (excess urinary protein excretion), as well as adverse changes in lipid peroxides and genetic transcription. Lim et al (71) demonstrated that taurine supplementation in diabetic mice was able to protect hepatic enzyme function from lipid peroxide formation. Trachtman et al (72) demonstrated that taurine supplementation is able to exert beneficial changes in the kidneys of diabetic rats, specifically reducing proteinuria and albuminuria by nearly half. This effect is attributed to the ability of taurine to decrease lipid peroxidation and reduce accumulation of advanced glycosylation end products within the kidney.

CANCER

In cancerous conditions, taurine is a potent cellular protective agent and immune enhancer. Researchers have discovered that taurine can inhibit tumors and extend the survival period of mice in which tumorous growth was initiated (73). When taurine supplementation was combined with a chemotherapy agent (cytoxan), the treatment yielded even more extended survival period with no tumor visible -- an inhibition rate of 100%. Tumor cell membrane fluidity was much improved with taurine treatment. The overall immune performance of taurine-treated animals was greatly improved over that of untreated counterparts.

Recombinant interleukin-2 immunotherapy is utilized as a treatment approach in certain types of cancers. However, it may produce a cytotoxic effect on both tumor cells and healthy vascular endothelial cells. When added to the cancer therapy program, taurine acts to reduce interleukin endothelial cell cytotoxicity without compromising the anti-tumor activity of immunotherapy. And, when used in conjunction with interleukin, taurine actually increases the tumor cytotoxicity. The calcium homeostatic mechanism of taurine was found to be the critical feature in these anti-cancer functions (74).

Hepatocarcinogenesis (cancer of the liver) is marked by changes in the lipid peroxidation capacity of the liver. When rats were exposed to carcinogenic substances without pre-supplementation with taurine, they experienced depressed glutathione peroxidase activity -- denoting a failure of antioxidation (75). Membrane stability was also compromised. Both the degree of membrane damage and the fall in glutathione function were reduced when oral taurine was given prior to exposure to carcinogens. This research suggests that taurine inhibits lipid peroxidation, thereby altering the activity of defense enzymes in the liver that can offer protection against membrane breakdown in hepatocarcinogenesis.

For the treatment of intraperitoneal (abdominal) tumors, researchers have studied taurolidine as both an alternative and an adjunct to heparin, a standard substance used to prolong the clotting time of blood. They found that tumor cell growth decreased significantly after administration of taurolidine and the combination taurolidine/heparin; heparin alone had no effect (76). It appears that taurolidine can produce a significant decrease in the growths of both tumor cells and intraperitoneal tumors.

Where a clearly defined therapeutic role for taurine may not be apparent, in certain cancers the amino acid profile yields useful data about the disease from which treatment approaches may be better assessed. Colorectal cancer patients exhibit a characteristic amino acid profile: significantly lower taurine, glutamine, valine, and tyrosine in plasma; significantly lower taurine, glutamic acid, methionine and ornithine intracellularly; and elevated valine, isoleucine, leucine, tyrosine, and phenylalanine intracellularly. Obtaining the amino acid profile may help to construct an appropriate dietary manipulation program aimed at modifying intracellular amino acid concentration (77). Likewise, squamous cell carcinoma of the head and neck exhibit a profile that is marked by decreased taurine, alanine, asparagine, aspartic acid, glycine, histidine, ornithine, phenylalanine, serine, and threonine, with a marked increase in levels of cystine. These features are noted regardless of the stage of the cancer and nutritional status. Thus, serum amino acid levels in serum and other tissues may become a useful cancer marker cancer and provide valuable prognostic information (78).

PRENATAL AND CHILDHOOD DEVELOPMENT

Starting with the health of the woman who seeks to bear children, through conception and fetal development, and ongoing through childhood growth, taurine is a vital substance that ensures proper maturation of the young. Taurine and other beta amino acids promote sperm motility, capacitation, and the acrosome reaction (activation of sperm to penetrate the egg cell). As a key organic osmolyte, membrane stabilizer, and antioxidant, taurine facilitates cellular function right from the first stages of embryonic development. Cell division means changes in cell number and cell volume. Deprivation of taurine to embryos in vitro proves to be taxing on cellular development, because they are left to rely on inorganic osmolytes for volume regulation and because the other advantageous cytoprotective functions of taurine are not available.

For the pregnant woman, magnesium sulfate is an established treatment for pre-eclampsia/eclampsia, where the fetus/infant suffers convulsions that are not attributable to epilepsy or cerebral hemorrhage. Magnesium taurate has recently been proposed as a superior alternative to magnesium sulfate. The protective action of magnesium and taurine individually against hypoxia may be combined to produce a substance that can prevent perinatal asphyxia, the leading cause of cerebral palsy (79).

Pregnant women consuming diets that are deficient in protein place their fetuses at risk for retarded growth. The human fetus needs taurine for all tissue development, yet is able to synthesize it only in very limited capacity. The primary source of amino acids for fetal development is the mother's dietary intake via placental transfer. Protein deficiency may impair placental transport of amino acids from the mother to the fetus. In a study of pigs, it was demonstrated that differences in females' cholesterol levels impacted fetal amino acid metabolism (80). It is speculated that deficiencies in fetal essential and nonessential amino acids caused by maternal dietary protein restriction causes a variety of fetal growth impairments. Studies of female rats also implicate lack of dietary protein in abnormal fetal development. Researchers report that, in vitro, taurine neither stimulated fetal islets nor responsiveness of fetal islets to other amino acids that are important to preventing the diabetic state. However, administration of taurine during gestation did promote insulin release equal to that of non-protein-deprived counterparts. Taurine is thus critical during development to produce normal fetal beta cell function (81). Indeed, the kidney is able to reduce kidney excretion in order to conserve taurine when availability via dietary uptake is low.

Taurine has a dose-dependent trophic effect on the human fetal brain cell, promoting proliferation and differentiation. Taurine also promotes the protein content of neuronal cells. Children diagnosed with minimal cerebral dysfunction are characterized by disturbances of the metabolism of amino acids. Specifically, they suffer from a decrease in the ratio of excitatory to inhibitory amino acids, depressed concentrations of both types of amino acids in the blood, and increased kidney activity to retain amino acids and prevent excretion. Fortunately, proper supplementation results with a recovery from the disturbed metabolic pattern.

Very specific patterns of taurine uptake emerge at different postnatal development stages. Researchers who studied the development of auditory function in full-term infants found that whole blood taurine concentration is decreased during the first four weeks of life, regardless of whether the infants ingested taurine-supplemented formula, non-supplemented formula, or breast milk. During this period, the auditory brainstem responses of the non-supplemented group were markedly shorter than the taurine and breast milk counterparts. This deliberate decrease in taurine levels is speculated to assist with the maturation and efficiency of auditory synapses (82). In low birth-weight infants, researchers have found that taurine supplementation up to the time of discharge from the hospital increased plasma taurine concentrations, yielding more mature auditory evoked responses as well as a healthier latency of the response interval than measurements found in non-supplemented counterparts (83).

Taurine is indispensable to proper neurological development and neuromuscular function. Reduction of the activity of placental taurine transporters, typical of intrauterine growth restriction, results in low plasma taurine concentrations, with subsequently compromised availability of the amino acid for cellular processes (84).

Taurine is necessary for the proper retinal development of children. Its presence prevents granulation of the retina. Its involvement in retinal cells changes during gestation. The developing human child undergoes a series of changes in the location of focused taurine activity in the eye, beginning at the 16^th week of gestation and proceeding through the 25^th week. In the postnatal infant and during subsequent development, taurine continues to dynamically influence the activity of the outer retinal area. These ongoing differences in the expression of taurine activity imply a critical and changing role in the development of vision (85).

Very low birth weight delivery complicates taurine availability to the infant. In these infants, the kidney is not yet fully developed and is unable to conserve taurine by enhancing renal reabsorption. As a result, these infants are at risk for taurine depletion more so than their larger pre-term or full-term counterparts. In its ability to promote fat emulsification via taurine conjugation of bile acids, dietary taurine intake is directly related to the ability to properly absorb lipids (86,87).

A number of chronic conditions may result from abnormalities in taurine levels in developing children. In neonatal cardiomyocytes (as with adult ones), taurine functions as an organic osmolyte. When taurine is lost, these cardiac cells reduce in size and change in shape as well as configuration. This adaptability of the cell's shape and size, in order to protect against tonicity fluxes, demonstrates the critical role of taurine in the regulation of osmotic balance (88).

Researchers have established characteristic amino acid profiles in children with severe liver disease. In children with cholestasis and those with cellular damage, decreases in taurine, glutamine, cysteine, tryptophan, serine, threonine and total and essential amino acids are compounded by increases in glutamic acid, ornithine, and citrulline. Children with cellular damage were shown to have increased tyrosine, phenylalanine and hydroxyproline. These findings are important markers of the metabolic abnormalities found in the pathology of liver diseases. In this particular study, the researchers were able to recommend a specific dietary support regimen to correct the taurine deficiencies in the cholestatic group (89).

In children with simple obesity, taurine supplementation triggers improvements in liver enzyme levels ("fatty liver"). Taurine is effective in this regard, independent of the success or failure of weight control measures. It also has benefit as an adjunct therapy in fatty liver associated with simple obesity (92).

Certain neurological disorders also correspond to characteristic amino acid levels as measured in the cerebrospinal fluid. While excitatory and inhibitory amino acids may be widely distributed across brain tissue, CSF amino acids reveal a different makeup. In bacterial meningitis and encephalitis, taurine levels are increased. This may be caused by a deliberate responsive effort by the cells of the central nervous system to modulate osmotic changes in these diseases by promoting increased taurine levels (91). While this finding provides insight into the pathology of meningitis and encephalitis, it remains to be seen whether administration of taurine has any value as a mode of treatment.

Abnormal levels of neurotransmitter amino acids are also found in autistic children. Glutamate and aspartate are elevated, whereas glutamine and asparagine are depressed. An increase in taurine may be deliberate, with the inhibitory action functioning as a compensatory calcium-dependent response to the elevated excitatory amino acids (92).

Sufficient levels of Vitamin B-6 must be available in order for adequate levels of taurine, glutamate, and GABA to be present in the brain. In Vitamin B-6 restricted rats, taurine, glutamine, and GABA were found to be significantly lower in concentration whereas glycine was notably higher. These changes were noted only in rats at 14 days old, the timeframe in which spontaneous seizures were observed. Neither the altered amino acid composition nor the occurrence of seizures was observed at older ages. This pattern of amino acid changes in the brain of these lab animals was coincident with measured changes in human models of the epileptic state (93).

A notable difference between breast-fed and formula-fed infants is in the disparity of brain phospholipid fatty acid composition that each feeding option produces. In fact, taurine is now added to many infant formulas to provide improved nourishment. This may have important physiologic functions yet to be elucidated. This supplementation is a wise proactive measure, given taurine's ability to improve fat absorption in pre-term infants and in children with cystic fibrosis and its beneficial effects on auditory response development (94). In pre-term infants, taurine supplementation of formula is important specifically to promote the absorption of vitamin D, a process found to be lagging compared to that of full term infants (95).

NEW APPLICATIONS

ALCOHOLISM

Some of the most novel applications for taurine result from studies of its role in alcoholism. Taurine can either promote or repress the reward effects associated with alcohol, the delineating factor being the amount of alcohol consumed. In a study designed to assess the preference of rats to alcohol coupled with an odor stimulus, the group that did not receive supplemental taurine became conditioned for either a significant aversion for the stimulus (prompted by high doses of alcohol) or no reaction (prompted by lower doses). When ethanol in a 2.0 g/kg dose was given to rats pretreated with oral taurine, they responded with a reduced aversion for a particular odor stimulus when paired with alcohol consumption. This may provide important insight into the modulation of the reward effect of alcohol (96). Previous studies had found that while taurine does not interact with alcohol to produce an effect on alcohol drinking, its major metabolite taurocholic acid is responsible for the metabolic conversion of alcohol.

From these careful observations of the correlation of taurine with alcohol consumption, scientists synthesized the drug acamprosate, the calcium salt of N-acetyl-homotaurinate. It is the first agent specifically designed to maintain abstinence in alcohol-dependent patients who have completed detoxification. It interacts with glutamanergic neurotransmission channels (NMDA receptors) to reduce calcium flux., resulting in a depressed interest in alcohol consumption (97). Acomprosate decreases glutamate elevations that are characteristic of alcohol withdrawal (98).

In a study of rats, researchers induced hepatic steatosis ('fatty liver') and lipid peroxidation by administering alcohol for a period of nearly one month (99). However, in the group in which taurine was co-administered, hepatic steatosis was greatly reduced and lipid peroxidation completely prevented. Fatty liver was prevented in animals receiving taurine supplementation. The protective effect of taurine was attributed to the potential of taurine conjugated bile acids (particularly taurocholic acid) to inhibit adverse enzymatic functions associated with alcohol consumption. This elucidates the very crucial tasks that taurine performs to protect against the deleterious effects of chronic alcohol consumption.

TO COMBAT EFFECTS OF AGING

Decline in taurine levels of the spleen, kidney, eye, cerebellum, and serum are associated with age in rats (100). Taurine supplementation effectively corrects these deficits. Urinary excretion of taurine is reduced with age, working to conserve taurine. Taurine may prove to be important in preserving normal muscle function that is ordinarily compromised with age. In a study of aging rats, depletion of taurine in skeletal muscle tissue causes decreases in both the electrical and contractile properties. Taurine supplementation significantly raised muscle taurine level, enhancing performance to that of a normal adult rat. Taurine also improves the mechanical threshold for contraction, shifting it toward the normal value (101). These findings may become applicable for the development of future novel therapies to combat age-related muscular decline.

FOR MIGRAINE

Researchers are now uncovering the underlying biological basis of migraine. Many of these identified activities -- neuronal hyperexcitation, vasospasm, hypoxia, platelet activation, and sympathetic hyperactivity -- can be expected to be countered by increased tissue levels of taurine and magnesium. Consequently, it is speculated that magnesium taurate may become a valuable drug to reduce migraine incidents (102).

FOR SEXUALLY TRANSMITTED DISEASE

The taurine-conjugate bile salt taurolithocholic acid 3-sulfate exerts a beneficial action in the prevention of sexually transmitted diseases (STD). By virtue of its detergent activity, taurolithocholic acid 3-sulfate demonstrates excellent anti-pathogen activity against chlamydia, herpes simplex (types 1 and 2), gonorrhea, and human immunodeficiency virus. It is also less cytotoxic than other agents used. Hence, taurolithocholic acid 3-sulfate may be a valuable topical STD microbiocidal agent (103).

TAURINE AS A MARKER OF DISEASE

In asthmatics, researchers have identified a characteristic profile that is present in bronchoalveolar lavage fluid. The chemical content of the fluid has been identified as primarily specific proteins, albumins and immunoglobulins, but it also contains amino acids and amino acid compounds. Taurine is significantly increased in asthmatic patients' fluid. Thus, the profile of amino acids in this fluid may serve as a potential diagnostic tool in the study of various pulmonary disorders (104). From this discovery, it may be possible to develop specific treatments targeted at modulating the profile of asthmatic bronchial fluid.

Major depression is marked by alterations in serum levels of the excitatory amino acids glutamate and aspartate, accompanied by deviations in levels of taurine, serine, and glycine as well. In patients who did not respond to treatment with antidepressants (treatment-resistant depression), characteristically lower serum levels of taurine, aspartate, asparagine, serine and threonine, with a steep increase in glutamine, were noted (105). These alterations may become valuable as diagnostic assessments to predict the response to treatment with antidepressants.

VISION DAMAGE DUE TO RADIATION

Taurine is a potent antioxidant in the eye, exerting a protective force on cell membranes that are subjected to attack by oxidizing free radicals. It is speculated that taurine, in binding with free radicals, protects ocular surface tissue from oxidative damage. It has also been found to be potentially useful in countering the damaging effects of low levels of gamma radiation, which affects the eye lenses in astronauts, jet crews, and military personnel assigned to radiation accident cleanup. A combination of taurine with vitamin E, vitamin C, and alpha lipoic acid has been shown to protect against radiation-associated protein leakage (106). Hence it may become important for the prevention of damage to the vision of people involved in these occupations.

ROLES FOR NEW TAURINE DERIVATIVE AGENTS

Taurolin is a potent chemotherapeutic agent that mobilizes anti-microbial activity against bacteria, yeast, and mycetes (fungi). Recently, a combined treatment of taurolin with vitamin E was shown to effectively decrease oxidative stress during peritonitis (an inflammation of the membrane lining the abdominal cavity) (107). The crossover benefits of this taurine derivative are just beginning to be discovered.

Taurolidine, a novel anti-microbial agent, is regularly used in Europe to prevent bacterial contamination in home parenteral-fed patients (those requiring nutritional support in liquid form due to inability to eat, feed, or absorb nutrients via the gastrointestinal tract). Low daily doses of taurine, instilled in conjunction with the parenteral infusion, has been shown to successfully reduce catheter-related bloodstream infections (108).

OTHER INTERESTING DISCOVERIES

Taurine release is enhanced by N-methyl-D-aspartate (NMDA), an agonist (promoter) of glutamate receptors. Nitric oxide is the messenger that prompts NMDA to evoke taurine release. Why is this important? To ensure the appropriate selection of medications based on receptor modulation. By understanding the role of excitotoxins and their inhibition by taurine, researchers hope to identify specific receptor-modulating agents that can target the underlying cellular triggers of conditions including trauma and disease of the brain. Nitric oxide generating compounds (L-arginine, potassium, anti-oxidants and fish oil) promote NMDA activity and, perhaps, taurine release. As researchers better understand the principles of excitotoxicity, the therapeutic value of these substances will increase (109).

As we forge great biotechnical advances that permit the introduction of artificial organs and promote speedier recoveries from hospitalization, scientists are challenged to optimize the use of these resources. Heart valves constructed of polyurethane are subject to fatigue from calcification. Taurine modification of the heart valves improves their durability by promoting and prolonging the flexing capacity over long-term use (110). In enteral feeding, feeding tube occlusion is a common and costly complication. The luminal content of the gut produces occlusive damage to enteral feeding tubes that are placed in the stomach or small intestine. The taurine-conjugated bile salt taurochlorate, exerting a detergent-like activity, markedly inhibits this occlusive action (111).

Connexins are a group of proteins that form the inter-membrane channels of gap junctions. While their specific role is not well understood, it is believed that connexins participate with the wide range of functions relating to intercellular communications. Taurine directly interacts with and modulates connexin channel activity (112). By probing a further understanding of the role of taurine, researchers may elucidate the structure and function of connexin proteins.

CLOSING REMARKS

From the first discovery of the role of taurine in vision, researchers have expanded their knowledge about this important sulfur amino acid. There is no lack of evidence derived from lab studies conducted on rats (where taurine is not essential), cats (where taurine is essential), dogs, and other animals. Admittedly, controlled studies on humans are lacking. However, sufficient animal and human research indicates the protective role of taurine in certain functions: cellular volume regulation and antioxidation are repetitive themes that have been borne out by years of study.

Taurine, either directly or indirectly, is able to exert either a proven or highly probable role in a number of diverse conditions that affect nearly every major organ or body system. This tiny molecule, not even officially classified as 'essential' in the definition of the word, is responsible for a wide variety of critical body processes. Most notably it promotes bile secretion and hepatic processes, cellular functions in the brain and retina, and optimizes cardiac and circulatory performance. Its concentration can vary in certain disease states, so measuring its levels may prove valuable as a diagnostic marker or prognostic gauge. Taurine has now garnered much respect in the medical and scientific arenas. The new applications of taurine and its derivatives hold great promise for preventative and therapeutic roles.

Taurine is a necessary and integral element for optimal health. Oral supplementation poses no major threat of toxicity, and its presence in foods makes it widely available to people seeking nutrition-oriented ways to improve their health. The importance of taurine cannot be overstated and its greater therapeutic application awaits only further research. It truly is part of the team of nutrients that we require for maintaining optimal health and sustaining life.

If, as William J. Mayo (founder of the Mayo Clinic) stated over sixty years ago, "the aim of medicine is to prevent disease and prolong life, [and] the ideal of medicine is to eliminate the need of a physician," it is then necessary to construct a new framework by which health care may be delivered. A health care system that is responsible in its procedures and responsive to its patients, that offers programs to address the body as a whole entity, enabling freedom from "dis-ease," is long overdue. Nutritional medicine, by employing a wide range of natural substances such as taurine, has great potential for helping health professionals to reach this ultimate level of health care. The physician must become the patient's partner in a long-term commitment to his/her personal health. A lifetime of optimal health awaits our patients if we help them implement a proactive health strategy that relies on gentle nutrients to nourish and rejuvenate from the inside out.

REFERENCES

Williams RJ, Heffley JD, Yew M, Bode C. "A Renaissance of Nutritional Science is Imminent," A Physician's Handbook on Orthomolecular Medicine, Williams RJ and Kalita DK, eds. New Canaan, CT: Keats Publishing, Inc., 1977.
Maar TE, Lund TM, Gegelashvili G, Hartmann-Petersen R, Moran J, Pasantes-Morales H, Berezin V, Bock E, Schousboe A. "Effects of taurine depletion on cell migration and NCAM expression in cultures of dissociated mouse cerebellum and N2A cells." Amino Acids, 1998;15(1-2):77-88
"USDA: Composition of Foods." USDA Handbook Number 8. Washington DC: Agricultural Research Service, USDA, 1976-1986.
Barada KA, Atallah JB, Nassar CF. "Age influence on intestinal taurine transport in mice." Comp Biochem Physiol A Physiol¸1997 Sep; 118(1) 159-63.
Trachtman H, del Pizzo R, Sturman JA. "Taurine and osmoregulation. III. Taurine deficiency protects against cerebral edema during acute hyponatremia." Pediatr Res, 1990 Jan; 27(1): 85-8.
Olson JE. "Osmolyte contents of cultured astrocytes grown in hypoosmotic medium." Biochem Biophys Acta 1999 Jan 6; 1453(1): 175-9.
Aruoma OI, Halliwell B, Hoey BM, Butler J. "The antioxidant action of taurine, hypotaurine and their metabolic precursors." Biochem J, 1988 Nov 15; 256(1): 251-5.
McCown TJ, Givens BS, Breese GR. "Amino acid influences on seizures elicited within the inferior colliculus." J Pharmacol Exp Ther. 1987 Nov; 243(2): 603-8.
Batuev AS, Bragina TA, Aleksandrov AS, Riabinskaia EA. "Audiogenic epilepsy: a morphofunctional analysis." Zh Vyssh Nerv Deiat Im I P Pavlova 1997 Mar-Apr; 47(2) 431-8.
Bac P, Pages N, Dhalluin S, Tapiero H. "Protective effect of Crassotrea gigas extract on audiogenic seizures in magnesium deficient mice." Biomed Pharmacother 1998; 52(4): 162-5.
Hilgier W, Zielinska M, Borkowska HD, Gadamski R, Walski M, Oja SS, Saransaari P, Albrecht J. "Changes in the extracellular profiles of neuroactive amino acids in the rat striatum at the asymptomatic stage of hepatic failure." J Neurosci Res 1999 Apr 1;

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