DNA-DAMAGING ACTIVITY OF THE CYPROTERONE-ACETATE ANALOGS CHLORMADINONE ACETATE AND MEGESTROL-ACETATE IN RAT-LIVER

The synthetic progestin cyproterone acetate (CPA) has been recently sh own to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the pres ent study we have examined the genotoxic potential of the structural a nalogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MG A) in rat liver cells, CPA strongly induced DNA repair synthesis in he patocyte cultures from females but not from males, In contrast, CMA an d MGA (2-50 mu M) did not detectably increase repair synthesis in cult ured hepatocytes from either gender, CMA and MGA, however, caused the formation of DNA adducts detectable by the P-32-postlabelling techniqu e. At a concentration of 30 mu M, between 30 and 50 adducts/10(9) nucl eotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/10(9) nucleotides were found in hep atocytes of males, By comparison, 30 mu M CPA had been found to produc e 1670 adducts/10(9) nucleotides in hepatocytes from female rats, CMA and MGA also induced low levels of DNA adducts in vivo. When female ra ts were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/10(9) nucleotides respectively, The results ind icate that both CMA and MGA show some genotoxicity in rat liver cells, which is, however, much lower than that for CPA, Our findings further suggest that the high genotoxicity of CPA is associated with the pres ence of the 1,2 alpha-methylene group, which is absent in CMA and MGA.