Cyproterone acetate generates DNA adducts in rat liver and in primary rat hepatocyte cultures.

Abstract

Cyproterone acetate (CPA), an active component of certain contraceptive and antiandrogenic drugs, has been shown recently to induce DNA repair synthesis in rat hepatocytes in vitro. In the present study we examined whether CPA can cause the formation of DNA adducts detectable by the 32P-postlabeling technique in hepatic cells in vitro and in vivo. Incubation of primary cultures of hepatocytes from male Wistar rats with CPA resulted in the occurrence of radioactive spots in the radiochromatograms of 32P-postlabeled DNA digests indicating the formation of two DNA adducts ('A' and 'B'). At 30 microM CPA, the highest concentration tested, approximately 50 'A' adducts and five 'B' adducts were found per 10(9) nucleotides. DNA of hepatocyte cultures from female rats was found to contain adduct A and a minor adduct termed 'D', but adduct B was not observed. Between 1 and 10 microM CPA, the relative level of adduct A was approximately 20-fold higher than the level observed in male hepatocytes. In vivo DNA adducts were detected almost exclusively in hepatic DNA. Hepatic DNA from male Wistar rats treated with single doses of CPA (1-100 mg/kg) by gavage, showed the major adducts A and B and two further spots of minor intensity ('C' and 'D') in the radiochromatograms. No adducts were detectable in extrahepatic tissues. The adduct pattern of liver DNA from females exposed to single oral doses between 0.1 and 30 mg CPA/kg body wt was similar to that observed in males; however, the relative levels for adducts A and D were approximately 100-fold higher. In females, linear relationships between dose and adduct levels were observed for all four adducts. The present findings show that CPA causes damage to hepatic DNA not only in vitro, but also in vivo. Thus it appears possible that DNA adduct formation is involved in the formation of hepatic tumors during long-term treatment of rats with the synthetic steroid.