acids – cysteine, glutamic acid, and glycine) ( Table 50.10 ). Glutathione conjugation produces water-soluble mercaptates which are excreted via the kidneys. The elimination of fat-soluble compounds, especially heavy metals like mercury and lead, is dependent upon adequate levels of glutathione, which in turn is dependent upon adequate levels of methionine and cysteine.
When increased levels of toxic compounds are present, more methionine is utilized for cysteine and glutathione synthesis. Methionine and cysteine have a protective effect on glutathione and prevent depletion during toxic overload. This, in turn, protects the liver from the damaging effects of toxic compounds and promotes their elimination.
Glutathione is also an important antioxidant. This combination of detoxification and free radical protection results in glutathione being one of the most important anticarcinogens and antioxidants in our cells, which means that a deficiency is cause of serious liver dysfunction and damage.
Exposure to high levels of toxins depletes glutathione faster than it can be produced or absorbed from the diet. This results in increased susceptibility to toxin-induced diseases, such as cancer, especially if phase I detoxification system is highly active.
Disease states due to glutathione deficiency are not uncommon. A deficiency can be induced either by diseases that increase the need for glutathione, deficiencies of the nutrients needed for synthesis, or diseases that inhibit its formation. For example, patients with idiopathic pulmonary fibrosis, adult respiratory distress syndrome, HIV infection, hepatic cirrhosis, cataract formation, and advanced AIDS have been found to have a deficiency of glutathione, probably due to their greatly increased need for glutathione, both as an antioxidant and for detoxification. Smoking increases the rate of utilization of glutathione, both in the detoxification of nicotine and in the neutralization of free radicals produced by the toxins in the smoke.
Glutathione is available through two routes: diet and synthesis. Dietary glutathione (found in fresh fruits and vegetables, cooked fish, and meat) is absorbed well by the intestines and does not appear to be affected by the digestive processes. Dietary glutathione in foods appears to be efficiently absorbed into the blood. However, the same may not be true for glutathione supplements.
In one study, seven healthy subjects were given a single dose of up to 3,000 mg of glutathione. Blood values indicated that the concentration of glutathione did not increase significantly, suggesting the systemic availability of a single dose of up to 3,000 mg of glutathione is negligible. The authors of the study concluded: “It is not feasible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.”
In contrast, in healthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to elevate and maintain good tissue glutathione levels. In one double-blind study, the average red blood cell glutathione concentration rose nearly 50% with 500 mg/day of vitamin C. Increasing the dosage to 2,000 mg only raised RBC glutathione levels by another 5%.
Vitamin C raises glutathione by increasing its rate of synthesis. In addition, to vitamin C, other compounds which can help increase glutathione synthesis include N-acetylcysteine (NAC), glycine, and methionine.
In an effort to increase antioxidant status in individuals with impaired glutathione synthesis, a variety of antioxidants have been used. Of these agents, only vitamin C and NAC have been able to offer some possible benefit. To determine the relative effectiveness of vitamin C vs. NAC, a 45-month-old girl with an inherited deficiency of glutathione synthesis was followed before and during treatment with vitamin C or NAC. High doses of vitamin C (500 mg/day or 3 g/day) or NAC (800 mg/day) were given for 1–2 weeks. Measurements of glutathione (GSH) levels indicated that 3 g/day of vitamin C increased white blood cell GSH fourfold and plasma GSH levels eightfold. NAC also increased white blood cell (3.5-fold) and plasma (two- to fivefold) GSH. Based on these results, it was decided that vitamin C would be given for 1 year at the 3 g/day dosage. At the end of a year, glutathione levels remained elevated and the hematocrit increased from a baseline 25.4 to 32.6% and the reticulocyte
count decreased from 11 to 4%. These results indicate that vitamin C can decrease cellular damage in patients with hereditary glutathione deficiency and is more effective than the more expensive NAC.
Over the past 5–10 years the use of NAC and glutathione products as antioxidants has become increasingly popular among nutritionally oriented physicians and the public. While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (e.g. AIDS, cancer patients going through chemotherapy, or drug overdose), it may be an unwise practice in healthy individuals. One study indicated that when NAC was given orally to six health volunteers at a dosage of 1.2 g/day for 4 weeks, followed by 2.4 g/day for an additional 2 weeks, it actually increased oxidative damage by acting as a pro-oxidant. Compared with controls, the concentration of glutathione in NAC-treated subjects was reduced by 48% and the concentration of oxidized glutathione was 80% higher. Oxidative stress increased by 83% in those receiving NAC.
Amino acid conjugation
Several amino acids (glycine, taurine, glutamine, arginine, and ornithine) are used to combine with and neutralize toxins ( Table 50.11 ). Of these, glycine is the most commonly utilized in phase II amino acid detoxification. Patients suffering from hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical exposure are commonly found to have a poorly functioning amino acid conjugation system. For example, using the benzoate clearance test (a measure of the rate at which the body detoxifies benzoate by conjugating it with glycine to form hippuric acid, which is excreted by the kidneys), the rate of clearance in those with liver disease is 50% of that in healthy adults.
Even in apparently normal adults, a wide variation exists in the activity of the glycine conjugation pathway. This is due not only to genetic variation, but also to the availability of glycine in the liver. Glycine and the other amino acids used for conjugation become deficient on a low-protein diet and when chronic exposure to toxins results in depletion.
Premenstrual syndrome, estrogen excess, cholestasis,OCA use
Methylation involves conjugating methyl groups to toxins ( Table 50.12 ). Most of the methyl groups used for detoxification come from S-adenosylmethionine (SAM). SAM is synthesized from the amino acid methionine, a process which requires the nutrients choline, vitamin B12 , and folic acid.
SAM is able to inactivate estrogens (through methylation), supporting the use of methionine in conditions of estrogen excess, such as PMS. Its effects in preventing estrogen-induced cholestasis (stagnation of bile in the gall bladder) have been demonstrated in pregnant women and those on oral contraceptives. In addition to its role in promoting estrogen excretion, methionine has been shown to increase the membrane fluidity that is typically decreased by estrogens, thereby restoring several factors that promote bile flow. Methionine also promotes the flow of lipids to and from the liver in humans. Methionine is a major source of numerous sulfur-containing compounds, including the amino acids cysteine and taurine.
Sulfation is the conjugation of toxins with sulfur-containing compounds ( Table 50.13 ). The sulfation system is important for detoxifying several drugs, food additives, and, especially, toxins from intestinal bacteria and the environment.
In addition to environmental toxins, sulfation is also used to detoxify some normal body chemicals and is the main pathway for the elimination of steroid and thyroid
hormones. Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders.
Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. Sulfation is also reduced by excessive levels of molybdenum or vitamin B6 (over about 100 mg/day). In some cases, sulfation can be increased by supplemental sulfate, extra amounts of sulfur-containing foods in the diet, and the amino acids taurine and glutathione.
Conjugation of toxins with acetyl-CoA is the primary method by which the body eliminates sulfa drugs ( Table 50.14 ). This system appears to be especially sensitive to genetic variation, with those having a poor acetylation system being far more susceptible to sulfa drugs and other antibiotics. While not much is known about how to directly improve the activity of this system, it is known that acetylation is dependent on thiamin, pantothenic acid, and vitamin C.
Glucuronidation, the combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl transferase (UDPGT) ( Table 50.15 ). Many of the commonly prescribed drugs are detoxified through this pathway. It also helps to detoxify aspirin, menthol, vanillin (synthetic vanilla), food additives such as benzoates, and some hormones. Glucuronidation appears to work well, except for those with Gilbert’s syndrome – a relatively common syndrome characterized by a chronically elevated serum
bilirubin level (1.2–3.0 mg/dl). Previously considered rare, this disorder is now known to affect as much as 5% of the general population. The condition is usually without serious symptoms, although some patients do complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function). The main way this condition is recognized is by a slight yellowish tinge to the skin and white of the eye due to inade- quate metabolism of bilirubin, a breakdown product of hemoglobin.
The activity of UDPGT is increased by foods rich in the monoterpene limonene (citrus peel, dill weed oil, and caraway oil). Methionine administered as SAM has been shown to be quite beneficial in treating Gilbert’s syndrome.
Sulfoxidation is the process by which the sulfur-containing molecules in drugs (such as chlorpromazine) and foods (such as garlic) are metabolized ( Table 50.16 ). It is also the process by which the body eliminates the sulfite food additives used to preserve many foods and drugs. Various sulfites are widely used in potato salad (as a preservative), salad bars (to keep the vegetable looking fresh), dried fruits (sulfites keep dried apricots orange), and some drugs (such as those used in the past for asthma). Normally, the enzyme sulfite oxidase metabolizes sulfites to safer sulfates, which are then excreted in the urine. Those with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine.
The strong odor in the urine after eating asparagus is an interesting phenomenon because, while it is unheard of in China, 100% of the French have been estimated to experience such an odor (about 50% of adults in the US notice this effect). This situation is an excellent example of genetic variability in liver detoxification function.
Those with a poorly functioning sulfoxidation detoxification pathway are more sensitive to sulfur-containing drugs and foods containing sulfur or sulfite additives. This is especially important for asthmatics, who can react to these additives with life-threatening attacks. Dr Jonathan Wright discovered several years ago that providing molybdenum to asthmatics with an elevated
TABLE 50-16-- Sulfoxidation
Sulfites, garlic compounds, chlorpromazine
Clinical indicators of dysfunction
Adverse reactions to sulfite food additives, garlic; asthma reactions after eating at a restaurant; eating asparagus results in a strong urine odor
Elevated urine sulfite/sulfate ratio
ratio of sulfites to sulfates in their urine resulted in a significant improvement in their condition. Molybdenum helps because sulfite oxidase is dependent upon this trace mineral. Although most nutrition textbooks believe it to be an uncommon deficiency, an Austrian study of 1,750 patients found that 41.5% were molybdenum-deficient.
One of the primary routes for the elimination of modified toxins is through the bile. However, when the excretion of bile is inhibited (i.e. cholestasis), toxins stay in the liver longer. Cholestasis has several causes, including obstruction of the bile ducts and impairment of bile flow within the liver. The most common cause of obstruction of the bile ducts is the presence of gallstones. Currently, it is conservatively estimated that 20 million people in the US have gallstones. Nearly 20% of the female and 8% of the male population over the age of 40 are found to have gallstones on biopsy and approximately 500,000 gall bladders are removed because of stones each year in the US. The prevalence of gallstones in this country has been linked to the high-fat, low-fiber diet consumed by the majority of Americans.
Impairment of bile flow within the liver can be caused by a variety of agents and conditions, as listed in Table 50.17 . These conditions are often associated with alterations of liver function in laboratory tests (serum bilirubin, alkaline phosphatase, SGOT, LDH, GGTP, etc.) signifying cellular damage. However, relying on these tests alone to evaluate liver function is not adequate, since, in the initial or subclinical stages of many problems with liver function, laboratory values remain normal. Among the symptoms people with enzymatic damage may complain of are:
Perhaps the most common cause of cholestasis and impaired liver function is alcohol ingestion. In some especially sensitive individuals, as little as 1 ounce of alcohol can produce damage to the liver, which results in fat being deposited within the liver. All active alcoholics demonstrate fatty infiltration of the liver.
Methionine administered as SAM has been shown to be quite beneficial in treating two common causes of stagnation of bile in the liver – estrogen excess (due to either oral contraceptive use or pregnancy) and Gilbert’s syndrome.
Liver detoxification support
Antioxidant vitamins like vitamin C, beta-carotene, and vitamin E are obviously quite important in protecting the liver from damage as well as helping in the detoxification mechanisms, but even simple nutrients like B vitamins, calcium, and trace minerals are critical in the elimination of heavy metals and other toxic compounds from the body.
The lipotropic agents, choline, betaine, methionine, vitamin B6 , folic acid, and vitamin B12 , are useful as they promote the flow of fat and bile to and from the liver. Lipotropic formulas have been used for a wide variety of conditions by nutrition-oriented physicians including a number of liver disorders such as hepatitis, cirrhosis, and chemical-induced liver disease.
Lipotropic formulas appear to increase the levels of SAM and glutathione. Although SAM is not currently available in the United States, methionine, choline, and betaine have been shown to increase the levels of SAM.
There is a long list of plants which exert beneficial effects on liver function. However, the most impressive research has been done on silymarin, the flavonoids extracted from Silybum marianum (milk thistle). These compounds exert a substantial effect on protecting the liver from damage as well as enhancing detoxification processes. Silymarin prevents damage to the liver through several mechanisms: by acting as an antioxidant, by increasing the synthesis of glutathione and by increasing the rate of liver tissue regeneration.
Silymarin is many times more potent in antioxidant activity than vitamin E and vitamin C. The protective effect of silymarin against liver damage has been demonstrated in numerous experimental studies. For example,
silymarin has been shown to protect the liver from the damage produced by such liver-toxic chemicals as carbon tetrachloride, amanita toxin, galactosamine, and praseodymium nitrate.
One of the key mechanisms by which silymarin enhances detoxification is by preventing the depletion of glutathione. Silymarin not only prevents the depletion of glutathione induced by alcohol and other toxic chemicals, but has been shown to increase the level of glutathione of the liver by up to 35%, even in normals.
In human studies, silymarin has been shown to have positive effects in treating liver diseases of various kinds, including cirrhosis, chronic hepatitis, fatty infiltration of the liver (chemical- and alcohol-induced fatty liver), and inflammation of the bile duct. The standard dosage for silymarin is 70–210 mg three times/day.
HEAVY METAL DETOXIFICATION
Nutritional factors which combat heavy metal poisoning include:
• a high potency multiple vitamin and mineral supplement
• minerals such as calcium, magnesium, zinc, iron, copper, and chromium
• vitamin C and B-complex vitamins
• sulfur-containing amino acids (methionine, cysteine, and taurine) and high sulfur-containing foods like garlic, onions, and eggs
• water-soluble fibers such as guar gum, oat bran, pectin, and psyllium seed.
Heavy metal toxicity and detoxification are discussed in detail in Chapters 18 and 37 .