Aflatoxins and Carcinogenesis Through Alkylation of Vitaletheine Modulators?

The following analyses provide a cohesive theory for explaining the carcinogenic potential of a variety of microbial and chemical toxins. The decrease in life expectancy for people residing in the US circa de 1993 indicates that there may be a resurgence of these problems brought on by an industrialization of our society and our food supply, including the warehousing of foodstuffs for strategic reserves and price controls. A return to a more "Victory Garden" mentality and the consumption of more raw foodstuffs may do more for our general health than medicines currently being developed. From this discussion, it appears that if one is saturated with any combinations of industrial, myco- and/or afla- toxins that destroy the vitaletheine modulators, then the potential for positive intervention with these promising new immunostimulants is severely compromised. Because of this, control of our environment and proper nutrition (prophylaxis) should receive as much emphasis for maintaining good health as is placed upon medical care.

Aflatoxin in Liver Cancer

Although there are individual researchers who are not convinced that aflatoxin is a carcinogen in man, the recent realization of just how important the vitaletheine modulators are to the immune system's ability to fight off cancer indicates otherwise. It is true that infection with hepatitis B virus seems to have a stronger correlation with the incidence of liver cancer than does exposure to aflatoxins in our foodstuffs. However, suppression of vitaletheine modulator-mediated immune responses by aflatoxin consumed in contaminated food by the general population may have a profound effect upon the epidemiology of hepatitis B viral infections, as well as upon risks for other types of infectious disease such as hantavirus, ebola, tuberculosis, cancer, AIDS, etc.. In this regard it is probably critical to the general health of the public that aflatoxins, known to be carcinogenic in laboratory animals, be minimized in our diets, especially when the biosynthesis of the vitaletheine modulators are otherwise compromised by dietary deficiencies and by exposure to other environmental toxins and carcinogens.

Probable Reactions of Carcinogenic Aflatoxins with the Vitaletheine Modulators

Aflatoxins can undergo many of the same reactions with sulfenic acids characteristic of reactions with dimedone or vitamin C. Adjacent keto- groups make any hydrogen on the intervening carbon acidic, favoring tautomerization of this structure to an enol. Like the enol tautomer of dimedone, these probably react with sulfenic acids to alkylate the sulfur, thereby generating a sulfide-linked adduct.

Possible Roles of Aflatoxins in a Variety of Diseases

These sulfides in turn can be oxidized in reactions catalyzed by monooxygenases, an activity that may contribute further to an uncoupling of the vitaletheine modulator/monooxygenase control of immunological responses. In this regard, it is interesting to note that the control of cholesterol feedback regulation studied by Siperstein also is lost, not only in spontaneous mouse and human liver tumors, but also in hepatoma caused by aflatoxin. This suggests that both high cholesterol (heart disease) and liver cancer have a common contributing factor in aflatoxin, a link that may be described in part by the observed interactions between HMG-CoA reductase and the monooxygenase thought to be the target for the vitaletheine modulators.

Among the aflatoxins, the structure of Q1 presents some interesting chemistry that may explain its relatively low carcinogenic potential. Because it is hydroxylated at a position in conjugation with the most likely site for thioalkylation with vitaletheine, this aflatoxin may be able to rearrange and spontaneously liberate vitaletheine so trapped. As a consequence of this, aflatoxin Q1 would be expected to be less carcinogenic than B1, just as ascorbate is less toxic than dimedone. Using a similar comparison, it is also interesting that dehydroascorbate is diabetogenic, hinting that thiols may form reversible adducts with the more oxidized versions of these bis-keto- structures. This last reaction, of course, would be subject to equilibration with other, more abundant thiols in the poisoned cells, such as glutathione and metallothionine that provide some protection for the vitaletheine modulators. The toxicity of dehydroascorbate is yet another reason to avoid high doses of vitamin C, since saturation of mechanisms for rereducing vitamin C that has autoxidized could lead to this and other mechanistically-related health problems. Some toxicity is still expected for the aflatoxin, Q1, since it appears to have some capacity to trap a second sulfenic acid (at the indicated position, "?"), and this reaction should effectively disrupt the conjugation responsible for the spontaneous liberation of trapped vitaletheine.

The seriousness of this interference of aflatoxin with sulfenic acid metabolism is illustrated by known effects of sulfenic acid formation, and the reaction of this sulfenic acid with dimedone, upon one of the key enzymes for energy production. Formation of a sulfenic acid on glyceraldehyde-3-phosphate dehydrogenase changes this energy-producing, enzyme system into an acyl phosphatase activity, essentially uncoupling the pathway for producing energy from sugar. Upon reaction of the sulfenic acid with dimedone, both activities of this enzyme are unrecoverably lost. This is very similar to an observed monooxygenase-dependent irreversible inactivation of HMG-CoA reductase with dimedone. Since the affected site in the dehydrogenase/acyl phosphatase seems to be a cysteine residue, aflatoxin (reacting in a manner similar to dimedone) could seriously compromise, not only the production of energy by this pathway, but also the availability of cysteine. This problem in turn compromises the biosynthesis and availability of the vitaletheine modulators. It would be interesting to determine if the AIDS virus, itself, or opportunistic infections of organisms capable of producing bis-keto- compounds (such as the Aspergillus flavus that produces aflatoxins) results in the observed symptomatology, i.e., low energy and weight loss, low plasma cysteine levels, and immunosuppression through these types of mechanisms.

Other Carcinogenic Mycotoxins that can React with Vitaletheine Modulators

There is already considerable evidence that mycotoxins produced by microorganisms in our foodstuffs constitute a serious threat to human health through likely reactions of their enols and epoxides with the vitaletheine modulators. Enol tautomers can be formed in ochratoxin A, patulin, and citrinin produced by Aspergillus-Penicillium. Trichothecens and zearalenone produced by Fusarium species are also capable of producing enol tautomers. The trichothecenes and vomitoxin, and the chemical warfare agent, nivalenol, in addition to having the capacity for enol tautomerism, have epoxide groups capable of reacting directly with the thiol forms of the vitaletheine modulators, as does T-2 and fusarenon X. Epoxides are also contained in the toxins, rioridin A, verracurol, verrucarin A, and muconomycin A. The profound effects that these compounds have upon immunity has been extensively reviewed by James J. Pestka and Genevieve S. Bondy.

Small-Molecular-Weight Carcinogenic Chemicals that can React with the Vitaletheine Modulators

While these mycotoxins tend to be rather complex organic molecules, there is evidence that even the simple epitopes within these compounds are carcinogenic. Consequently, these simple compounds should be eliminated from our industrialized societies whenever and wherever possible. Proprionolactones, ethylene imines, and epoxides have all been identified as carcinogenic substances that react with thiols. Incubations with thiols, or the amino acid cysteine, inactivate the carcinogenic potential of many of these substances, confirming what is probably a sparing effect upon the vitaletheine modulators. Although direct reactions with the thiol moieties of the vitaletheine modulators can account for most of the observed toxicities of the compounds in this particular article, mechanisms involving the monooxygenase system must be evoked to explain the toxicities of a few of those mentioned.

Analysis of Carcinogenic Potential Based Upon Oxidation States

According to the above-referenced article, maleic anhydride reacts with cysteine and produces tumors in rats, but sodium maleate is not carcinogenic. Likewise, the thiol reagent, N-ethylmaleimide, is not carcinogenic. The "thiol" reagent, N-ethylmaleimide, probably reacts immediately with glutathione in the cell that serves to protect any vitaletheine modulators that might happen to be in the thiol form. The vitaletheine modulators are expected to be mostly in their oxidized forms due to reactions driven by the monooxygenase, so sulfenamides are more likely products of reactions of such amines with the vitaletheine modulators. Sulfenamides formed in this manner can be easily hydrolyzed, for example, to N-hydroxy-maleimide and the corresponding free thiols. The carcinogenic maleic anhydride, on the other hand, may undergo an initial reaction of thiol with its carbonyl-conjugated alkene to form a sulfide. The resulting sulfide and enol tautomer then can react with a sulfenic acid moiety, say of the vitaletheine modulator family, to form a bis-sulfide adduct. According to the above scenario, glutathione might activate the carcinogenic potential of maleic anhydride, while sulfenic acids of the vitaletheine modulator family would preferentially react with this enol-tautomer-containing sulfide product. An adduct containing a sulfide of each, one glutathione and one vitaletheine moiety, is expected. Also consistent with this theory is the observation that succinic anhydride, lacking the carbonyl conjugation found in maleic anhydride, is not carcinogenic. Reaction of succinic anhydride with thiols should produce only a thiol ester, probably that of glutathione, that is easily hydrolyzed by endogenous thiolesterases to regenerate the free thiol. Consequently, succinic anhydride is far less likely than maleic anhydride to react with the sulfenic acids of the vitaletheine modulators, perhaps accounting for the observed differences in the carcinogenic potential for these two substances.

This theory, that compounds capable of reacting with sulfenic acids to produce stable sulfides are carcinogenic through their ability to alkylate the sulfur of the vitaletheine modulators, finds some support in the well-known tumor-promoting activities of phorbol esters.

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