DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver

The synthetic progestin cyproterone acetate (CPA) has been recently shown to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the present study we have examined the genotoxic potential of the structural analogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MGA) in rat liver cells. CPA strongly induced DNA repair synthesis in hepatocyte cultures from females but not from males. In contrast, CMA and MGA (2-50 μM) did not detectably increase repair synthesis in cultured hepatocytes from either gender. CMA and MGA, however, caused the formation of DNA adducts detectable by the 32 P-postlabelling technique. At a concentration of 30 μM, between 30 and 50 adducts/109 nucleotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/109 nucleotides were found in hepatocytes of males. By comparison, 30 μM CPA had been found to produce 1670 adducts/109 nucleotides in hepatocytes from female rats. CMA and MGA also induced low levels of DNA adducts in vivo. When female rats were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/109 nucleotides respectively. The results indicate 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 presence of the 1,2a-methylene group, which is absent in CMA and MGA.