Copyright © 1996, 1997, 1999, 2000, 2001 by Galen Daryl Knight and VitaleTherapeutics, Inc.

Nutritional Requirements for Monooxygenase

Analysis of receptors for biologically active substances often provide key information about how biological systems are controlled. In the case of the microsomal flavin-containing mixed-function monooxygenase, proposed as a receptor for the vitaletheine modulators, there is an interesting array of nutrients and cofactors necessary for this enzyme's activities, including niacin, riboflavin, oxygen, and probably pantothenic acid and cysteine. It is no small coincidence that decades ago these vitamins were recognized as essential for proper humoral (antibody) immune response. The key to appreciating the significance of this phenomenon is the realization that stimulation of immune responses can be used effectively against cancer and other diseases only when all of the components necessary for the humoral and cell-mediated responses are optimized, including the newly discovered vitaletheine modulators. Although the above list now appears to be a fairly comprehensive one, there is evidence that other, as yet unconfirmed, nutritional factors are essential for the maintenance and proper functioning of the monooxygenase; rats maintained on defined diets supplemented with vitamins and minerals have significantly lower concentrations of this liver enzyme than controls fed a standard (and more nutritionally complete) laboratory chow.

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:

  1. When administered in drinking water, high concentrations of vitamin C should have a significant presence of autoxidation products.
  2. Partially oxidized ascorbate is known to inhibit HMG-CoA reductase, and it is reasonable to assume that this artifact might help to prevent tumor growth.
  3. Unfortunately, completely reduced ascorbate uncouples the down-regulation of HMG-CoA reductase and may increase the growth of some tumors, including melanomas, by chemically reducing regulatory sulfenic acid intermediates.
  4. Fully oxidized or dehydro-ascorbate is considered to be diabetogenic.
  5. There is recent evidence from a study of healthy (emphasis on "healthy") human males that vitamin C saturates when supplements of about 200 mg are taken daily and immunocytes are saturated by only 100 mg daily; one gram/day (1000 mg/day) or more can needlessly cause health problems.
The authors of this last study are to be commended for helping to dispel the notion that grams of vitamin C should be taken daily to maintain health. However, based upon our concerns about the potential negative effects of vitamin C upon immune response, tumor growth, and monooxygenase activity, we question their apparent assumption that saturation of tissues with vitamin C is desirable in healthy individuals and their subsequent conclusion that the RDA should be increased to 200 mg/day. Most enzymic systems are designed to function at less than saturating levels of substrate, i.e., in the sigmoidal part of saturation curves, to ensure the greatest range of flexibility for biological responses without the detrimental accumulation of substrate or products of the reaction; this is especially true of signal transduction and amplification pathways. Although we agree that some increase in the RDA for vitamin C may be warranted, apparently neutrophils, monocytes and lymphocytes saturate with regimens of about 100 mg daily. When one considers the advantages of having a dynamic or flexible (not quite completely saturated) immune response, perhaps the current RDA of 60 mg is still reasonable as a recommendation for a daily dietary supplement, at least until it can be established that the proposed 200 mg daily dose has no detrimental effects upon hemolytic plaque responses and other immune parameters affecting human health. Hemolytic plaque responses are a measure of cytolytic antibody production that may be effective against cancer, and viral and other infectious diseases.

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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