HEPATIC ZONATION OF THE INDUCTION OF CYTOCHROME-P450 IVA, PEROXISOMALLIPID BETA-OXIDATION ENZYMES AND PEROXISOME PROLIFERATION IN RATS TREATED WITH DEHYDROEPIANDROSTERONE (DHEA) - EVIDENCE OF DISTINCT ZONAL AND SEX-SPECIFIC DIFFERENCES

Dehydroepiandrosterone (DHEA) is an intermediate product in the synthe sis of male and female sex hormones in the adrenal cortex of man, In l ivers of rats and mice DHEA increases the levels of cytochrome P450 IV A and peroxisomal beta-oxidation enzymes associated with peroxisome pr oliferation. Prolonged treatment of rats with DHEA induces liver tumor s that are more frequent in females arising mainly in the periportal r egions of the liver lobule (Metzger et at, Toxicol, Pathol. 23, 591-60 5, 1995), Because of paucity of information on hepatic zonation of per oxisomal response to DHEA and controversial reports on gender-specific differences of its effects the present study was undertaken using qua litative immunohistochemical and quantitative immunoelectron microscop ical techniques in addition to Western blotting, Rats were treated for 24 weeks with 0.6% DHEA supplied with diet, Immunoblot analysis revea led marked induction of peroxisomal beta-oxidation enzymes, which by q uantitative analysis was equally strong in male and female animals, wh ilst catalase and urate-oxidase mere not increased, Cytochrome P450 IV A, in contrast, was induced significantly stronger in male than in fem ale rats, Immunohistochemistry confirmed the induction of cytochrome P 450 IVA showing a marked Lobular gradient in female animals with stron g induction in pericentral and almost no induction in periportal regio ns of the liver lobule, In male animals cytochrome P450 IVA was expres sed more uniformly across the liver lobule, A similar sex specific zon e-dependent response was observed for peroxisomes. DHEA induced in fem ales a significant zonal gradient with marked peroxisome proliferation and a strong induction of peroxisomal hydratase/dehydrogenase in peri central hepatocytes and a much smaller response in periportal regions. Livers of male animals, in contrast, showed a uniform peroxisomal pro liferation to DHEA with only slight zonal differences, The striking ho mologies of the induction patterns of cytochrome P450 IVA and the pero xisome proliferation in both sexes support the notion of a functional relationship, In view of the almost exclusive periportal localization of DHEA-induced tumors in female rats in contrast to the pericentral l ocalization of the peroxisomal proliferation shown by this study, it s eems likely that other factors in addition to peroxisome proliferation may contribute to the hepatocarcinogenic effect of DHEA.