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

The synthetic steroid cyproterone acetate (CPA) has been reported to be hep atogenotoxic in female rats depending on sex-specific expression of a hydro xysteroid sulfotransferase (HST) which is involved in the bioactivation of CPA to reactive metabolites. In the present study the ability of CPA to ini tiate apoptosis in rat hepatocytes lit vitro was investigated with respect to sex-specific effects and dependency on HST activity. Incubation of prima ry hepatocytes of female rats with CPA (0.1-30 mu M) caused a strong increa se in percent of cells undergoing apoptosis, The lowest concentration leadi ng to apoptosis was 0.3 mu M In contrast, hepatocytes isolated from male ra ts showed a very weak response at high exposure to CPA (30 mu M) only. Trea tment with transforming growth factor-pr induced high levels of apoptotis i n hepatocytes of both genders. Megestrol acetate and chlormadinone acetate, two structural analogues of CPA with a much lower genotoxic potency, did n ot induce apoptosis, Pre-addition of 10 or 50 mu M dehydroepiandrosterone ( DHEA), a known inhibitor of hepatic HST, almost completely inhibited CPA-in duced apoptosis in hepatocytes of female rats. Using similar test concentra tions, DHEA also reduced CPA-induced DNA excision repair as measured in the unscheduled DNA synthesis test. The results suggest that apoptosis inducti on is directly related to DNA damage induced by HST-dependent CPA metabolit es.