Possible Mechanisms of Action for Chemical Warfare Gases

Interference with the vitaletheine modulator system may help to explain the diverse symptomatology known as the "Gulf War Syndrome". Since every cell tested to date is stabilized by vitalethine when the cell is deprived of a normal supply of its specific peptidyl hormone , destruction or interference with the vitaletheine modulator/monooxygenase system would be expected to produce diverse symptomatology, the symptoms manifesting themselves first in the least vigorous of an individual's tissues.

Phosgene has the capability of turning virtually every free amine in the body into an analogue of the carbamate/carbonimidic moiety of the vitaletheine modulators. In so doing, it can cause competitive inhibition of a variety of systems regulated by these compounds.

HN1, HN2, Lewisite 1, Mace, and Mustard Gas "H" all have the capacity to alkylate the sulfur of the vitaletheine modulators. This toxic mechanism is not limited to war gases, since alkyl halides, and haloalkenes, are readily produced by the reaction of chlorine and other halines (such as those added to our drinking water and swimming pools) with organic material. Other problematic environmental exposures include ethylene dichloride, ethylene dibromide, trichloroethylene, chlorotrifluoroethylene, and hexachlorobutadiene. All of these compounds can alkylate thiols to form alkyl sulfides , substances known to be substrates for the monooxygenase. One particularly relevant example of this is the S-alkylation of cysteine, an amino acid of protein and of glutathione that normally is not a substrate for the monooxygenase; one product of such an alkylation is S-benzyl-L-cysteine , a known substrate for the monooxygenase and a structure not far removed from the one expected from a reaction of Mace with cysteine or the vitaletheine modulators .

It seems odd that other alkylating agents used to treat cancer are almost uniformly carcinogenic, themselves. This seems to be counter-intuitive, the equivalent of giving an alcoholic another drink to calm DTs. However, drastic measures such as these may be necessary in rapidly growing tumors to slow tumor growth so that the immune system has a few weeks to a month to "catch up" and "manage" any residual tumor cells. The key to long-term survival on the other hand may be immune stimulation after the "anti-neoplastic" agents have cleared the system, such as that provided by the vitaletheine modulators, to increase immunological screening for any tumor cells that may have escaped the alkylating therapy and any new tumors that may result from the alkylating therapy.

The cysteamine moiety of the vitaletheine modulators is actually contained within the structure of cimetidine (Tagamet) and ranitidine (Zantac) as sulfides. As noted elsewhere on this site cysteamine and these H-2 antihistamines are known substrates for the monooxygenase. The extremely toxic chemical warfare agent, VX, also contains an imbedded cysteamine moiety as its sulfide. Fortuitously, we often use "V" to designate vitaletheine such as in "VSH" and the polymer "V4", and "VX", through its structural homology with the seemingly non-toxic vitalethine, may be appropriately named, figuratively and literally, as a "V" antagonist ("X"). In fact, other sulfides and secondary and tertiary amines, known to be substrates for the monooxygenase thought to be the receptor for the vitaletheine modulators, are well-represented in the chemical warfare agents . HN1, Mustard Gas "H", and even Lewisite 1 have chemical characteristics typical of substrates for the monooxygenase and /or for reacting with thiol forms of the vitaletheine modulators. Although Tabun and VX have the dubious distinction of also being likely substrates for the monooxygenase, at least some of the toxicities of Sarin, Soman, Tabun, and VX are probably due to an inhibition (perhaps irreversible) of kinase activity such as the pantothenate kinase proposed as a crucial step in the biosynthesis of Coenzyme A and the vitaletheine modulators. Coenzyme A is essential for the biologicial processing of nearly all forms of energy (fat, carbohydrates, protein, and even alcohol). Consequently, these phosphate analogues might interfer with both, the Kreb's cycle and with oxidative phosphorylation, to produce the chronic fatigue symptoms characteristic of "Gulf War" exposures.

Even more troubling is the probability that the chemical warfare agents block the final step in the biosynthesis of vitaletheine. Crude preparations of 4'-phosphopantetheine, thought to be the immediate precursor of vitaletheine , protect the monooxygenase against inactivation by a snake venom pyrophosphatase . This toxic enzyme probably lyses the pyrophosphate bond in FAD, thereby destroying an essential cofactor for the monooxygenase and its activity. Binding of 4'-phosphopantetheine to the active site on the monooxygenase probably prevents this hydrolysis of cofactors and the destruction of the monooxygenase's activity. It follows that 4'-phosphopantetheine is probably a substrate for the monooxygenase and that its resulting sulfenic acid can rearrange to vitaletheine on the enzymes active site. Vitaletheine produced in situ in this manner may, in turn, be oxidized to its sulfenic acid and even to its disulfide, vitalethine, by known monooxygenase-catalyzed reactions. There is even some evidence that vitalethine, the product of further oxidation by the monooxygenase, co-purifies with the monooxygenase, indicating a tenacious affinity of this enzyme for vitalethine. Chemical warfare agents containing moieties that are substrates for the monooxygenase, analogues of cysteamine, and/or suicide analogues of the phosphate in 4'-phosphopantetheine clearly have the capacity to destroy any endogenous production and activity of the vitaletheine modulators.

What can be done to off-set exposures to chemical warfare agents or the "gulf war syndrome"? It is now known that deficiencies of either protein (cysteine?) or of vitamins and minerals important to the synthesis of the vitaletheine modulators can lead to immune suppression . The logical first step on the road to recovery is to ensure an adequate supply of the nutrients critical to our immune system and other functions. These must include adequate protein (cysteine) and vitamins, especially the B vitamins. A "good diet" of industrialized foods, alone, may not be adequate for these purposes, and supplementation with vitamins and minerals likely will be necessary to re-equilibrate ones system. (See our "nutrition" link, below, for more information and evidence for these conclusions). Why is this a logical first step? Because it is inexpensive, it is not likely to do any harm, and supplementing with appropriate levels of vitamins and minerals should only improve ones health, according to most of the carefully-controlled nutritional research that has been conducted to date.

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