GSH AND DETOXIFICATION

TOXINS, GLUTATHIONE AND HEALTH

Medical science and public health measures have notably reduced death rates and prolonged the average life span, especially in developed countries. But development has its downside. Our environment contains tens of thousands of confirmed toxic substances, and the pace of life and consumeroriented marketing promote bad lifestyle habits which we all adopt to some extent. We in the twentieth-century can expect a longer life span than our ancestors, but one potentially burdened by chronic ailments. The full promise of longevity is blunted.

What's remarkable is that we don't succumb even earlier to the daily onslaught of toxins in our food, air and water. We have our body's defense mechanisms to thank, notably the GSH detoxification process. But like all biological systems, even this can be overwhelmed by extensive or prolonged attack and may eventually begin to function poorly.

Although GSH was discovered in 1888 by De-Rey-Pailhade, it was not until the 1970's that its detoxifying role was recognized. Over the past thirty years scientific understanding of this process has unfolded slowly, but the huge resurgence of interest in preventive medicine and in GSH is giving rise to new discoveries. The liver and the kidney are the major organs of detoxification and elimination and have the highest levels of intracellular GSH in the body. GSH is the most important thiol (sulfurcontaining amino-acid) in living systems. It plays a critical role not only in humans and mammals, but in all vertebrates and even in insects, plants and micro-organisms.

H. Lew and A. Quitanihila, physiologists at the University of California, verified the upside of this discovery. The increased liver GSH levels seen in actively trained, physically fit individuals leave them better equipped to handle toxic threats from such substances as acetaminophen. R.J. Flanagan and T.J. Meridith at the Poisons Unit of Guy's Hospital in London reviewed the use of N-acetyl-cysteine (NAC)-a GSH-enhancing drug-as a detoxifying treatment. They believe that besides its common use as a treatment for acetaminophen overdose, research will show its potential to detoxify the body of carbon monoxide, carbon tetrachloride, chloroform, and other harmful compounds.

PREVENTION

A serious shortcoming of traditional medicine is its focus on treatment rather than prevention. This isn't without cause. The need to see people who are sick or suffering is always more pressing than the good intention to meet those in good health. And there's no shortage of disease out there-if anything, there's a shortage of doctors. It has fallen to other branches of the healing arts to address the issue of maintaining well-being. Nutrition-sensitive approaches can teach us a great deal. But the real strength of such health maintenance is self-awareness. We must study for ourselves, and learn to take control of the conditions that affect our well-being. As much as possible, we should avoid whatever harmful influences we can, then identify the unavoidable ones and provide our body with whatever resources it needs to fight them.

SMOKING AND TOBACCO

Medically, statistically and economically, the greatest risk to health in North America is tobacco use. The huge body of scientific evidence accumulated over the past decades leaves no doubt that cigarette smoking profoundly increases the risk of contracting Chronic Obstructive Pulmonary Disease (COPD, including asthma, chronic bronchitis and emphysema), cancer and cardiovascular disease. Despite years of successful lobbying and denial, the tobacco industry has recently been forced to admit what the medical community has known for ages-cigarettes kill.

Cigarette smoke releases thousands of different chemicals and a single puff contains literally trillions of free radicals. The smoke actually burns away antioxidant vitamins like C and E and other nutrients, but even worse is the inflammation it causes in the lungs. This is the principal source of oxidative stress. The degree of lung inflammation and injury is directly related to the extent of oxidation caused by cigarette smoke. In addition, the tar from tobacco products contains potent carcinogens that cause not only lung cancer but all sorts of other tumors. GSH is well known to scavenge these free radicals and to neutralize many of the toxins by conjugation and elimination. If you're not ready to quit smoking, or if you can't avoid second-hand smoke, elevated GSH levels will help protect you.

Many studies have outlined the role of GSH in preventing or suppressing the damage caused by smoking. Clinicians have even gone as far as attempting to treat some of these consequences -not just prevent themwith glutathione-enhancing drugs like NAC. 

RADIATION

Ionizing radiation is a known cause of cancer, and does other kinds of harm as well. It is one of the most extensively studied of all carcinogens and accounts for about three percent of all cancers. Some radiation comes from natural sources such as cosmic rays and natural radioactive minerals. The most common source is sunlight, which carries the increased threat of ultraviolet radiation due to depletion of the protective ozone layer. Other sources include nuclear waste from energy plants, industrial waste, weapons test residue and certain building materials. X-rays from radiographs, mammograms, CT scans and other medical test equipment are all weak, but have a cumulative effect over time.

Exposure to radiation results in the formation of hydroxyradicals-the most reactive of all free radicals. Many studies have shown that GSH plays a key role in its neutralization. Some physicians are raising GSH levels of patients in radiotherapy. This tends to reduce the side-effects they experience and can even enhance the effectiveness of the therapy itself.

L.A. Applegate at the Swiss Institute for Experimental Cancer Research conducted studies on human cells cultured in the laboratory. First, his team depleted their glutathione levels with the drug BSO, then they exposed the cells to radiation. They found a significantly higher proportion of DNA mutations, and therefore an increased risk of developing cancer. J. Navarro and a team of Spanish doctors showed that humans exposed to radiation suffered from significant GSH abnormalities.

V .N. Bhattathiri led a research team in India to study patients suffering from oral cancer. Each patient's GSH levels were measured before radiation therapy and correlated to the side-effects of the therapy. It was clear that the lower their initial GSH levels, the more injury they suffered. Following these tests the team felt able to identify any patient's susceptibility to radiation damage by measuring their GSH levels. They recommended that treatment dosages be adapted to the individual's ability to withstand the therapy.

A group of genetic researchers at the University of Nurnberg in Germany studied the potential use of NAC (a GSH-enhancing drug) to protect human white blood cells from X-ray damage. Cells pretreated with NAC clearly had a protective advantage over untreated ones. Glutathione and its role in cancer, chemotherapy, and radiotherapy is discussed in chapter cancer.

Enhanced GSH levels can also reduce the damaging effects of sunburn. It is believed that skin damaged by sunburn can develop various forms of skin cancer. Chapter at reviews some important studies relating to sun exposure, ultraviolet-radiation damage and glutathione.

HEAVY METAL TOXICITY

Heavy metals are metals from periodic table groups IIA through VIA. The semi-metallic elements boron, arsenic, selenium, and tellurium are often included. Many are essential in small quantities but can accumulate to toxic levels. Absorbed from the environment and food chain, they gradually build up in biological systems-from plants to the human body-and can grow into a significant health hazard. Such metals as arsenic are actually used as poisons. Nutritional supplements like iron or medications like bismuth are helpful or essential at appropriate doses, but quickly become toxic at higher levels. Here is a list of potential heavy metal toxins:

Heavy metals exert their influence on all sorts of tissue and can affect many bodily systems. The nervous system, the renal (kidney) system, the cardiovascular (heart and circulation) system, the hematological (blood) system, the gastrointestinal (digestive) system and many others are affected one after the other. Heavy metals exact their damage by generating free radicals or by interfering biochemically with normal metabolic functions.

Glutathione and its associated enzymes help regulate and eliminate many of these metals. Clinical studies have outlined the role of GSH in heavy metal toxicology and its role has been described in the way cells process arsenic, arsine, bismuth, cadmium, chromium, cobalt, copper, gold, iron, lead, mercury, nickel, selenium, silver, thallium, tin, vanadium and zinc. Of all these substances, mercury seems to be the most GSH-depleting.

MERCURY TOXICITY

The heavy metal mercury is an insidious but potent toxin that warrants special attention. It is all too common in our environment and is fraught with controversy, most notably when the topic of mercury amalgams (dental fillings) comes up. I have seen usually staid and sober medical and dental professionals coming close to blows over this issue at educational conventions. However, one of the tenets of the Hippocratic oath is, "Above all, do no harm." There certainly is sufficient clinical evidence to force a much closer look at the use of this important neurotoxin in clinical applications.

Mercuric substances can be either organic or inorganic. Inorganic forms include pure or elemental mercury (quicksilver), or the salts of mercury (mercuric chloride, mercuric oxide and others). These can be inhaled or ingested. High-risk occupations include dentistry, manufacture of batteries, explosives and jewelry, photographic development and taxidermy. Organic mercury comes in many forms, methyl-mercury being the most commonand also highly toxic. Poisoning by this form usually follows accidental ingestion. Farm workers, embalmers and producers of pesticides, fungicides, insecticides, bactericides, drugs and preservatives are all at risk.

Although primarily a neurotoxin (nerve poison), mercury can cause a broad range of problems, including kidney failure, severe nausea and vomiting, diarrhea, oral lesions (stomatitis), lung inflammation (pneumonitis) and rashes. It affects the nervous system with symptoms as subtle as emotional instability, anxiety, memory loss, and lethargy. The expression "Mad as a hatter" has an interesting basis in fact. Hat-makers in the nineteenth century used elemental mercury to form and weigh down their hats, and often paid a high neurological price for repeatedly handling this toxin. Serious mercury poisoning includes tingling or loss of sensation in the extremities, poor coordination, tremors, slurred speech and tunnel vision. These symptoms can progress to paralysis, coma and death.

Traditional treatment of mercury toxicity requires binding of the metal to larger organic molecules, a process called chelation. Chelating agents may be administered orally (e.g. D-penicillamine), intra-muscularly (e.g. Dimercaprol, BAL) or intravenously. Once chelated, the mercury complex is eliminated through normal excretion of urine or stool.

It has been long known that glutathione is a primary cellular defense against mercury toxicity. It starts out by effectively quenching the formation of free radicals. Even more critical is its ability to bind directly to mercuric compounds, enabling the cell to expel and the body to excrete them.

A recent article from the International Archives of Occupational and Environmental Health measured the impact of mercury exposure on glutathione levels. Forty-two workers from a chloralkali factory exposed to elemental mercury were compared to seventy-five non-exposed workers from a lime production plant. As expected, blood levels of mercury were higher in mercury workers, but so were levels of lipid peroxidation. Evidently, the detoxifying effects of glutathione peroxidase were significantly decreased.

In the laboratory, many studies have shown how glutathione protects cells from toxicity. By raising GSH levels, a team of toxicologists from the University of Arizona was able to decrease mercury-induced kidney damage. An Argentinean team had equal success using NAC to preserve renal (kidney) function. Similar positive results were found using glutathione monoester, selenium, and other agents to enhance GSH levels.

Experimentation on the liver, nerve and small intestine and other tissues, and even in fetal development verify that mercury drains the glutathione system, that decreased GSH levels lead to increased toxic damage by mercury, and that elevating or sustaining glutathione significantly protects cells against mercury poisoning.

DENTAL AMALGAMS

There's quite a controversy surrounding the alleged ill-effects of mercury from dental fillings (amalgams). The mercury in these so-called `silver' fillings makes them malleable and strong. It has been a mainstay of dentistry for decades. Studies show that for average individuals not otherwise exposed to mercury, these filling represent the predominant source of exposure. The same studies also indicate that urinary mercury excretion is significantly higher in individuals with these fillings, and that these excretion levels correspond to the amount of filling in their mouths. A German study determined that the longterm excretion of mercury could be cut by five-fold after amalgam removal. A recent study from the journal of Dental research by G. Sandborgh-England concluded that "...the process of removing amalgam fillings can have a considerable impact on Hg (mercury) levels in biological fluids."

The sixty-four thousand dollar question is whether or not this higher level of mercury exposure actually produces ill-effects. A recent study by the Australian W Blumer, looked at 80 patients with dental amalgams who also showed symptoms of chronic mercury toxicity. Using the chelator EDTA to flush mercury from the body, it was found that the urine of patients with fillings had significantly higher levels of mercury. The fillings were removed and patients continued to take oral chelators along with selenium supplementation (to raise glutathione peroxidase). After three months patients were either symptom-free or greatly improved.

Proponents of the amalgam-toxicity school of thought are seeking ways to detoxify both patients and the dental professionals who are exposed daily to mercury vapors. Merely removing the exposure is not enough-like other heavy metals, mercury remains imbedded intracellularly in deeper tissues unless appropriately chelated or removed.

NAC (N-acetylcysteine) raises GSH levels and has been used to detoxify organic mercury. Researchers from the Department of Environmental Medicine at the University of Rochester, NY showed that oral NAC profoundly accelerates urinary methylmercury excretion to levels as much as ten times more than usual. NAC is able to detoxify mercury compounds.

One of the foremost scientists dealing with heavy metal and mercury toxicity is Dr. David Quig of Chicago, Illinois. He has elaborated the interplay of mercuric compounds, glutathione, cysteine and other metallothioneins (organic metal-sulfur compounds). He feels the long-term effects of consistent low-level mercury exposure have been underestimated. According to him, the most effective way to eliminate these toxins from deep tissue like the brain is by eating high-quality whey protein. Although the bioactivity of natural whey can easily be denatured, good quality whey protein can have significant GSH-enhancing properties. Studies using undenatured whey protein are currently underway by several research groups. The protein precursors of GSH act here as oral chelating agents.

High levels of mercury poisoning are often treated by emergency dialysis (blood filtration). American military doctors at their Health Sciences Department of Pharmacology at Bethesda, Maryland carried out an experiment to improve this treatment, with revealing results. Using dialysis they investigated the ability of ten different chelating agents to remove mercury from blood fluid. Most kidney specialists were surprised to find that NAC was very effective, even surpassing more traditional agents. Clinicians are now starting to apply this knowledge to their daily practice, using GSH therapy as a complement to their usual emergency treatments.

CASE STUDY

Sheryl was a 32-year-old mother of four who had fallen ill following the caesarian delivery of her last child two years earlier-the surgical incision was taking far too long to heal. Her gynecologist was puzzled and noted some muscular atrophy. She experienced periods of such profound weakness that she was bedridden for days. Over the next 18 months this weakness recurred and she was eventually admitted to hospital. Various diagnoses were considered, including multiple sclerosis and chronic fatigue syndrome, but supportive treatment for these conditions didn't help. Then her dentist suggested that mercury toxicity might be a contributing factor so she had her mercury amalgams removed.

Herbal supplementation was attempted to rid her of residual mercury. Her symptoms improved modestly. Some internet research led the dentist to undenatured whey protein, which he suggested to Sheryl. Within five days she experienced a marked increase in strength. After ten days she

was walking without pain. Two weeks later she rode her bike for the first time in 2,'/z years. Three weeks later, she felt "almost back to normal." She still feels well and continues to raise an active family.

LEAD POISONING

Plumbism-lead poisoning-is a public health problem that dates back to Roman times. The name comes from the use of lead (Latin: plumbium) in plumbing. Other forms of exposure have been common for centuries through cooking and eating utensils, pottery, and the use of lead in paints (fortunately discontinued in most house-paints). Moonshine liquor is sometimes prepared using automobile radiators, pipes and barrels soldered with lead. Mechanics, battery manufacturers, solderers and other tradespeople are subject to occupational exposure.

Lead poisoning is often difficult to diagnose. The symptoms can be subtle and very non-specific. Nevertheless, acute poisoning can be accompanied by severe nausea and vomiting, diarrhea, kidney failure, seizures, coma, paralysis, and death. Continuous, repeated exposure can result in anemia, weakness, aches and pains and irritability, not to mention a host of intellectual dysfunctions from learning disabilities to profound mental behavioral changes. The treatment is removal of the source of exposure and chelation therapy.

Like mercury, lead is detoxified at the cellular level by the glutathione enzyme system. The pro-oxidant effect of lead is counterbalanced by the antioxidant capabilities of GSH and the lead molecule itself can be conjugated or bound to glutathione, after which it is eliminated from the body.

Lead toxicity affects many tissues including the central and peripheral nervous system, the liver, the kidneys and red blood cells. Depleted GSH stores usually indicate increased severity of the disease. Restoration of glutathione levels is protective and helps eliminate lead. Raising GSH levels with agents like NAC, and the use of selenium have been shown to be a useful complement to traditional therapies, acting at the level of the liver, kidney, red blood cells and even the lens of the eye to counteract the deleterious effect of lead poisoning.

The anemia (loss of red blood cells) that is characteristic of lead toxicity is caused by several different factors, among them high levels of oxidative stress. This leads to lipid peroxidation of the red blood cell membrane, followed by cell disruption. A Japanese research group studied workers with a high occupational lead exposure by measuring their lipid peroxidation levels, lead concentration and glutathione peroxidase activity. The results show that lead levels and peroxidation levels seem to be directly related, and levels of the essential GSH-peroxidase fell as lead levels rose.

ENVIRONMENTAL ILLNESS

Chronic exposure to xenobiotics (substance foreign to the body) may lead to subtle and hard-to-pinpoint changes in health, and may also lead to full-blown syndromes known as Environmental Illnesses (EI). These often reveal themselves in a combination of minor complaints-such as headaches, fatigue and lethargy-that tend to confuse diagnosis. They may be quite profound, as in the case of MCS (multiple chemical sensitivity) which has only recently become accepted as a legitimate diagnosis. For similar reasons, it was years before the medical community recognized Gulf War Syndrome as a specific illness.

There are many sources of xenobiotic exposure around the home. Carpets may hide pesticides carried in on footwear; steamy bathrooms contain chloroform; dry-cleaned clothes hanging in your closet give off fumes of perchloroethane and trichloro-ethane; fireplaces produce benzene and household cleaners contain paradichlorobenzene. In the office, photocopy toner releases formaldehyde and styrene, among other chemical pollutants. Enclosed parking garages are another source of benzene, among other chemicals. The air outdoors in the city or even the country contains many different compounds that we should ideally avoid. And of course, rooms in which people are smoking tobacco contain dozens of carcinogens and other toxic chemicals. We should be careful when using mildew removers, mothballs, scented detergents, fabric softeners, lawn fertilizers, pesticides, solvents and cleansers, paints, heating fuels, certain insulation materials and even products used to manufacture mattresses and furniture.  Fortunately, a wealth of published information can help you keep track of these substances and where they are used. You'll find some excellent guides at your local bookstore.

Because the number of poisons in the general environment is large, exposure to environmental pollutants is unavoidable. In addition, concentrations of specific substances are high in certain workplaces. In an article on chemical toxicity in industrial workers, D.V Parke and A. Sapota made a powerful statement about threats that can be counteracted by GSH. They claim that many industrial workers with symptoms of systemic inflammation are often misdiagnosed as suffering from rheumatoid arthritis, viral infections, connective tissue diseases and other such maladies. Physicians need to be informed more thoroughly about the ability of chemical pollutants to imitate inflammatory diseases.

Exposure to certain chemicals in the workplace has been connected to the development of cancer. R.K. Ross and his colleagues at the University of Southern California linked a deficiency of GSH enzymes to bladder cancer in workers exposed to arylamines-are also present in cigarette smoke.

CONCLUSION

The number of toxins our bodies must deal with every day is truly remarkable. To cope with this burden a fit, rested, well-fed person must maintain adequate immunological and biochemical defenses. The role played by GSH in these defense systems cannot be overstated. Glutathione detoxifies a large number of pollutants, carcinogens, heavy metals, herbicides, pesticides and radiation. We are exposed every day to toxins like cigarette smoke, automobile exhaust, food preservatives and dental amalgam and our body depends on GSH for their removal. Substances that raise GSH levels are being used with increasing frequency in the field of toxicology with considerable success.

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