Cytochrome P-450s as toxicogenic catalysts: the influence of dehydroepiandrosterone

The cytochrome P-450s catalyze the oxidative transformation of a large number of endogenous and exogenous chemicals in plants, insects, and mammals. One consequence of this type of reaction is the generation of highly reactive electrophilic metabolites that can react with intracellular macromolecules. It has been postulated that the initiation reaction for chemical carcinogenesis and/or cellular toxicity involves the metabolism of xenobiotics by P-450s. The naturally occurring steroid dehydroepiandrosterone (DHEA), when administered as a supplement to the diet of rodents, has been reported to have anti-carcinogenic and other chemoprotective activities. A change in the inventory of liver P-450s occurs during treatment of rodents with DHEA, the most pronounced being that involved in the omega-hydroxylation of medium-chain length fatty acids. In addition, changes in the activities of other liver P-450s, viz., P-450IIB1, P-450IIC11, and P-450IIIA, occur as shown by in vitro experiments to assess the P-450-dependent formation of hydroxylated metabolites of testosterone and androstenedione. The effect of feeding rodents a diet supplemented with DHEA mimics some of the changes seen when animals are treated with hypolipidemic drugs (such as ciprofibrate, and other chemicals which are known to be peroxisome proliferators). Studies comparing the enzymatic functions of the heterologous expressed recombinant forms of P-45017 alpha, responsible for the two step conversions of progesterone and pregnenolone to the C19-steroids, androstenedione, and DHEA, respectively, illustrated the marked differences in enzymatic properties between the human and the rat orthologues. The findings serve to demonstrate that DHEA is an obligatory intermediate for the synthesis of androgens in the human, but not in the rodent. The biochemical changes responsible for the anti-carcinogenic properties of DHEA remain to be identified. The studies presented here suggest that DHEA, when administered as a dietary supplement, functions like a xenobiotic, and that its effects may result from alterations in the inventory of cellular P-450s, thereby influencing the balance of metabolic activities associated with the initiation phase of chemical carcinogenesis and/or toxicity.