Importance of metabolism in chemical carcinogenicity

IT IS GENERALLY ACCEPTED that chemicallv induced carcinogenesis is initiated by the interaction either of the compound itself or a reactive metabolite thereof, with nuclear DNA leading to somatic mutation in the target cells. Apart from a few direct-acting compounds, most carcinogens in man's chemical environment require metabolic activation to exert their biological effects (Miller, 1970) and animal studies have shown that species sensitivity and the susceptibility of target organs to a carcinogen can he influenced by the dose, form and route of exposure, tissue distribution, metabolic activation and detoxi-fication processes, stability of reactive meta-bolites formed and the receptivity of crucial intracellular sites. Other factors known to modulate the metabolic disposition of carcinogens are age, sex, strain, nutritional and hormonal status and genetic deficiency (Conney & Levin, 1974). Thus an understanding of the metabolic fate of a carcinogen is bound to be of value in the extrapolation of animal data to man. Certain of these factors will be considered in relation to the metabolic activation of carcinogens in general, and of dimethylnitro-samine and other N-nitrosamines in particular. Dimethylnitrosamiine (DMN), a potent and versatile carcinogen in a wide range of animal species, requires metabolic transformation to exert its toxic and carcinogenic effects (Magee & Barnes, 1967). Studies in the rat and other animal species have shown that DMN is rapidly metabolized in the intact animal (Heath, 1962) and that the liver is the principal organ involved in the bioactivation of this nitrosamine (Magee & Vandekar, 1958). Investigations on liver preparations have revealed that DMN degradation is mediated by the microsomal fraction, and that NADPH and molecular oxygen are essential co-factor requirements (Venkatesan et al., 1970). This finding has led to the conclusion that the bioactivation of DMN to eletrophilic species is mediated by the hepatic microsomal mixed-function oxidase (MFO) system centred on cytochrome P-450. However, an accumulating body of experimental evidence indicates that the metabolic activation process involved in DMN degradation may be more complex, and not mediated solely by the MFO enzyme system. Earlier studies had shown that pretreatment of 497