Before addressing specific examples of nutritional regulation of these systems, an additional note on the flavin-containing monooxygenase is necessary. A variety of other substances known to influence monooxygenase-catalyzed reactions, such as fatty acids (inhibitors), increased levels of glutathione (uncoupler), and phosphatidyl inositol phosphates (inhibitors), are either predisposing in general or are associated with a particular form of cancer. For example, enyzmes producing phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5 bis-phosphate can increase up to 28 and 45 times, respectively, in liver cancers, especially in rapidly growing ones. Hence, pathological perturbations of the flavin-containing monooxygenase and vitaletheine modulator system need not be direct, and can arise from metabolic imbalances or even genetic anomalies in other biochemical pathways. The good news is that corrections of lesions in these other pathways and efforts to restore the monooxygenase and vitaletheine modulator system should have complementary therapeutic benefits.
Cysteine, an amino acid found in most protein, and vitamin B5 (pantothenic acid) are probable building blocks for the vitaletheine modulators. Thus, diets rich in these nutrients normally should provide the raw materials for making the vitaletheine modulators. The importance of protein in maintaining the immune system is well-established, and diets deficient in methionine, a supplier of sulfur for the synthesis of the disulfide (cystine) when cysteine is also limiting, have even been associated with poor regeneration of wounded tissues.
Other earlier studies indicated that protein promotes cancer, but these were conducted using supplementation with a major protein of dairy products. Casein is a poor source of cysteine since only one of its three forms have any cysteine at all. The cravings for dietary protein, therefore, may have been satisfied in these animals long before there was adequate cysteine intake. Diets in these early studies also are suspected of being contaminated with aflatoxin that would further deplete cysteine, a building block for the vitaletheine modulators. Finally, it is entirely possible that the sulfide product of the reaction of aflatoxin with cysteine or with the vitaletheine modulators are nonproductive or diversionary substrates for the monooxygenase with undesirable consequences.
Niacin is a term applied to a source of this B vitamin that is usually nicotinic acid, but can be nicotinamide. Names such as vitamin B3 or B4 are now obsolete because of confusion with other factors such as pantothenic acid, which also has been referred to as vitamin B3. Niacin is used as a building block for Nicotinamide Adeninine Dinucleotide Phosphate (known as NADPH in its reduced form and as NADP+ when oxidized). NADPH is an essential substrate for the monooxygenase thought to serve as an important receptor for the vitaletheine modulators.
Riboflavin or vitamin B2 is a building block for Flavin Adenine Dinucleotide (FAD), and FAD is another essential cofactor for the monooxygenase. It is interesting that riboflavin and its coenzyme forms (once thought important in activating potent carcinogens like aflatoxin B1, benzo[a]pyrene, and azodyes) may actually provide some protection against these carcinogens and neoplastic disease.
Oxygen is an essential substrate for the monooxygenase that may be in short supply in the center of a rapidly growing tumor and in other pathological conditions.
Although Ascorbic Acid (vitamin C) has been shown to increase (induce) the amount of monooxygenase, this might be a compensating mechanism for another more ominous activity of this vitamin. Excessive daily doses of this vitamin (about 2 g/kg/day) reportedly are prophylactic in about half of mice inoculated with uniformly deadly melanoma, but there is little to no evidence in this study that vitamin C is effective against incipient or established melanoma. Probable artifacts (following) not addressed in this study make it difficult to determine if the benefits of such high doses of ascorbate outweigh their potential for harm:
Several other nutrients are of interest for their possible roles as antioxidants. Vitamin E is a fat-soluble vitamin and melatonin is a fat-soluble hormone that decrease lipid peroxidation in membrane fragments. This is important since lipid epoxides are known to react with thiols and it doesn't take much lipid epoxide to chemically inactivate femtogram and picogram/kg concentrations of the vitaletheine modulators.
Vitamin E is of particular interest for its ability to diminish background (or non-specific) oxidative reactions. Other isoprenoid-like antioxidants and unsaturated long chain hydrocarbons might interfere with the actions of vitamin E if the beneficial response is mediated though a biological receptor. This type of competitive phenomena might help to explain recent results in a large population of smokers that led to serious questions about the benefits of beta-carotene in cancer prevention.
Melatonin, another potent antioxidant available for the time being without a doctor's prescription, is of interest as a supplement for individuals over 40, for some cancer patients, and for others having trouble sleeping. Melatonin is usually produced by the pineal gland (the third eye) and by other tissues in response to darkness. Stimulation of immunity has been observed in vivo, but melatonin in cell culture has an inhibitory effect upon immune responses, results consistent with possible interactions with the monooxygenase. The production of this antioxidant and sleep-facilitating hormone decreases with age and levels are low in individuals with at least some forms of cancer. Since prolonged exposure to light inhibits melatonin's production, light pollution in industrialized societies (including late-night television and Web crawling) also may deplete this important antioxidant, thereby predisposing individuals to disease.
Benefits derived from melatonin supplements pose some interesting social questions. Will the public allow the medical and pharmaceutical professions to usurp control of this substance? Are dietary sources of melatonin important, and do fashionable dietary recommendations, such as a restricted consumption of red meat and fat, deprive us of this hormone? Unfortunately, melatonin in the diet now probably partitions into the fat of meats along with environmental carcinogens and preservatives such as ethoxyquin.
That being said, melatonin should not be taken by certain individuals without first consulting with a health professional: pregnant or lactating women, children unless a deficiency is established, persons with medical conditions requiring prescription steroids or monamine oxidase (MOA) inhibitors, women trying to conceive, and individuals with severe mental illness or allergies. Until we have a better working knowledge of how our immune systems respond to melatonin and to the vitaletheine modulators, individuals with autoimmune diseases or immune system cancers such as leukemia and lymphoma should also thoroughly discuss the matter with their doctor before using melatonin; any insomnia in this last group of individuals, however, might be reason enough for both the doctor and patient to be interested in melatonin supplements.
It is not known if indoles found to induce other monooxygenases have any effect upon the flavin-containing microsomal mixed-function monooxygenase, nor is it known if the reported diurnal variation in thiol and disulfide ratios is in some way linked to both, the latter monooxygenase activity and the diurnal production of melatonin. Expect the etiology of many diseases to be made clearer in the near future if it turns out that melatonin controls the expression of the flavin-containing monooxygenase.
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