The Role of Hepatic Metabolism in Sex Differentiation of Chemical Hepatocarcinogenesis in the Rat

Abstract

Male rats show a much faster growth rate of enzyme-altered hepatic foci than female rats during selection/promotion of diethylnitrosamine-initiated cells with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH) in the resistant hepatocyte model (RH-model). Hepatocellular carcinomas are also formed with a much shorter latency period in male than in female rat liver. In the present study nodular tissue from male and female rats was compared with respect to some reactions towards steroid and xenobiotic substrates that are sex differentiated in surrounding and control rat liver. The total content of cytochrome P-450 was decreased in late nodules from both male and female rats, exhibiting 51% and 72% of the content in the surrounding liver, respectively. No decrease in the total content of cytochrome P-450 was seen in early nodules compared to liver from non-initiated rats treated with 2-AAF/PH. The sex difference in 16α-hydroxylation of 4-androstene-3, 17-dione was markedly attenuated with microsomes from nodular tissue, mainly due to a decreased formation in microsomes from male nodules, compared to surrounding tissue. Western Blot analysis with monoclonal antibodies towards two sex specific forms of cytochrome P-450, active in steroid metabolism, revealed that the male-specific cytochrome P-45016α was decreased in male nodules compared to surrounding liver. On the other hand cytochrome P-45015β seemed to be increased in male nodules compared to surrounding liver whereas the level was high in both nodular and surrounding female liver. N,O-sulfation of N-hydroxy-2-acetylaminofluorene, a sex differentiated pathway in the metabolism of 2-AAF (♂>♀) suggested to be important for the promotive effects of 2-AAF, was decreased both in early and late male nodules compared to control/surrounding liver. The sulfotransferase activity was low in all preparations from female rats. An early decrease in N,O-sulfation might be important for the selectively faster growth rate of enzyme-altered foci in male than in female rat liver observed in the RH-model.