Sex-specific induction of apoptosis by cyproterone acetate in primary rat hepatocytes.

Abstract

The synthetic steroid cyproterone acetate (CPA) has been reported to be hepatogenotoxic in female rats depending on sex-specific expression of a hydroxysteroid sulfotransferase (HST) which is involved in the bioactivation of CPA to reactive metabolites. In the present study the ability of CPA to initiate apoptosis in rat hepatocytes in vitro was investigated with respect to sex-specific effects and dependency on HST activity. Incubation of primary hepatocytes of female rats with CPA (0.1-30 microM) caused a strong increase in percent of cells undergoing apoptosis. The lowest concentration leading to apoptosis was 0.3 microM. In contrast, hepatocytes isolated from male rats showed a very weak response at high exposure to CPA (30 microM) only. Treatment with transforming growth factor-beta1 induced high levels of apoptotis in hepatocytes of both genders. Megestrol acetate and chlormadinone acetate, two structural analogues of CPA with a much lower genotoxic potency, did not induce apoptosis. Pre-addition of 10 or 50 microM dehydroepiandrosterone (DHEA), a known inhibitor of hepatic HST, almost completely inhibited CPA-induced apoptosis in hepatocytes of female rats. Using similar test concentrations, DHEA also reduced CPA-induced DNA excision repair as measured in the unscheduled DNA synthesis test. The results suggest that apoptosis induction is directly related to DNA damage induced by HST-dependent CPA metabolites.