Depletion of coenzymes at the site of rapidly growing tissues due to alkylation: the biochemical basis of the teratogenic effects of alkylating agents, including organophosphorus and certain other compounds [proceedings

Abstract

Attention has been drawn (Schoental, 1976) to the possibility that alkylating agents, whether those which release their alkylating entities chemically or those which require preliminary metabolic activation, will deplete the tissue concentration of coenzymes, because they will alkylate, among other items, the reactive nucleophilic groups in the latter. When the alkylating entities are released in the hepatocytes, the predominating effects will be liver damage in the centrilobular areas, where the concentrations of the B vitamins become first exhausted. Foetal and other rapidly growing tissues have a lower concentration of coenzymes than the respective adult tissues (Kaplan, 1966; Ferris C muscular hypoplasia was induced in the chick embryos, which could be prevented by nicotinamide. Similarly the presence of 3-acetylpyridine in chick-embryo mesodermal cell cultures will give rise to cartilage; when nicotinamide is added to the culture medium muscle cells will develop preferentially (Caplan et al., 1968), and the decrease in NAD coenzymes in the tissues will be prevented (Rosenberg & Caplan, 1975). Differentiation in foetal tissues growing in uitro appears to be affected by the integrity and concentration of NAD coenzymes. Certain organophosphorus and methyl carbamate compounds can induce abnormalities in the chick embryo, the severity of which correlate with the degree of depletion of NAD coenzymes. Nicotinamide will prevent the depletion of the coenzymes and most of the abnormalities (Proctor & Casida, 1975). The mechanism of action of the organophosphorus compounds remained unexplained. I suggest that the teratogenic effects of the organophosphorus compounds and the decrease in NAD coenzymes is related to the alkylating potentialities of the respective substances. Phosphoric esters can undergo hydrolysis (with the loss of an alkoxyl group), and also dealkylation (with the release of an alkyl group) (see Heath, 1961 ; O’Brien, 1967; Hollingworth, 1969; Hilgetag & Teichmann, 1971, and references therein). The alkylating activity of the various organophosphorus compounds for the nucleophilic 0-, Sor N-groups correlates with the acidity of the remaining part of the molecule, and decreases in the following order: (RO),P(O)H >(RO),P(O)>(RO),P(O)R ROP(0)RZ. It appears surprising that although the alkylating ability of organophosphorus compounds has been known for many years, i t has usually been disregarded in the considerations of their biological action. We have suggested that the ‘dying-back’ neuronal degeneration caused by certain organophosphorus compounds depends also on the depletion of coenzymes owingto substitution oftheir reactivesites by thegroups released from the neurotoxic phosphate esters and deficient replacement (Schoental & Cavanagh, 1977). This view is supported by the fact that B-vitamin deficiencies per se can cause the ‘dying-back’ neuropathies (Cavanagh, 1964) and also teratogenic effects (see Hughes, 1976, and references therein). Though, at present, evidence points mainly to the depletion of NAD coenzymes, other B vitamins containing coenzymes (FAD, CoA, folates, pyridoxal phosphate, thiamin pyrophosphate etc.) are likely also to be implicated in foetal abnormalities, but have not yet been appropriately investigated. If my suggestions should prove justified, it may become possible to prevent the