Monooxygenase Control of HMG-CoA Reductase and Oncogenic Expression

The relationship between monooxygenases and HMG-CoA reductase is important for several reasons. First of all, monooxygenases that catalyze the oxidations of thiols have the potential for controlling cancer which is dependent upon isoprenylation of ras, both at the reductase step by blocking the production of isoprenyl (mevalonate) units and later in the actual isoprenylation step by modifying (oxidizing) the cysteine residues of ras to preclude isoprenylation. By decreasing HMG-CoA reductase activity and the production of mevalonate, monooxygenase activity also can control the biosynthesis of cholesterol from mevalonate, a contributing factor in heart disease. The importance of sulfur metabolism in controlling cholesterol is illustrated by the observed decrease in dietary cholesterol, increase in HDL (the good cholesterol), and decrease in triglycerides in rats fed diets enriched in either cysteine or cystine, as either the amino acids or protein. Since cysteine is not a substrate for the monooxygenase, in order for cysteine to work in the following pathway, it must first be decarboxylated to metabolites on the Coenzyme A through cysteamine pathway, which should include members of the vitaletheine modulator family. The vitamin, pantothenic acid, is required for this to happen.

Individuals suffering from cystinosis, or some types of kidney stones, probably should not supplement their diets with cystine or cysteine. There are some indications in the literature that pantothenic acid supplements alone may benefit this health problem by helping to metabolize the accumulating cysteine and cystine to cystamine. If cystinosis is not a problem, then supplements of either cysteine or cystine can be considered. Cystine may be safer in the sense that it probably does not extract heavy metals from any stainless steel processing equipment (used in the preparation of the supplement) as readily as the more common cysteine supplement (especially the HCl salt). In other words, the "cysteine" supplements theoretically can pick up more heavy metals in their preparation than the disulfide. However, cysteine (alias thiol- or reduced form, -SH, or sulfhydryl) may provide more protection against aflatoxin and other carcinogenic and toxic mycotoxins that contaminate our food supply by reacting with these carcinogenic substances before they are absorbed. In the case of cysteine, this probably first requires autoxidation to its sulfenic acid, explaining the low rate of reaction between cysteine and aflatoxin and how cysteine can be slowly depleted from our food supply by contaminating mycotoxins.

Since the monooxygenase is unstable in the absence of NADPH and NADP+, a deficiency of niacin (from which these cofactors are made) may be particularly disruptive to this enzyme and its ability to down-regulate HMG-CoA reductase. Also, if results in the "test tube" are any indication, the absence of oxygen should lead to dramatic losses of the monooxygenase when NADPH is adequate. In other words, under hypoxic (or low oxygen) conditions thought to exist in the center of rapidly growing tumors, NADPH may aggravate the regulatory problems caused by the loss of monooxygenase activity by directly favoring activities of HMG-CoA reductase. When excessive, this unregulated mevalonate synthesis can contribute to heart disease (high cholesterol) and to tumor proliferation (isoprenylation reactions). These relationships provide rational explanations for two previously puzzling phenomena:

Depriving tumor cells of oxygen in culture is known to make them more malignant (intractable) when inoculated into laboratory animals.
Despite the fact that niacin is used to make the NADPH cofactor for the reductase, this vitamin is better known for its ability to lower, not increase, cholesterol.

With these considerations, niacin should be most useful in the prevention of cancer and heart disease, especially in tobacco users. If rapid tumor growth can be controlled by other means and if the tumor tissue can be adequately oxygenated, niacin may have some therapeutic value even in large tumors. There is similarly guarded therapeutic potential in advanced heart disease, as well, since arteries occluded by proliferation of the endothelium lead to poorly oxygenated tissues, just as rapidly growing large tumors outstrip their oxygenated blood supply. Because of similarly linked difficulties in these two diseases, pathological proliferation and poor aeration of tissues, several complementary and even alternative therapies for the vitaletheine modulators are of interest, including hyperbaric oxygen, gene therapy increasing expression of the monooxygenase in poorly oxygenated tissues, and proliferation-suppressing agents that might have a sparing effect upon revascularization and reoxygenation of tissues.

GO TO:

Home	Overview	People	Journal	Nutrition
Environment	Treatments	WWW Links	Outline	e-mail us