Accumulation and persistence of DNA adducts of the synthetic steroid cyproterone acetate in rat liver.

Abstract

Cyproterone acetate (CPA) is a synthetic steroid which is widely used in antiandrogenic and gestagenic drugs. We have recently shown that CPA induces DNA adducts in cultured rat hepatocytes and in rat liver (1). In the present investigation, we studied the persistence and accumulation of CPA-derived DNA adducts in the liver of rats using the 32P-postlabeling technique. To study the persistence of CPA-DNA adducts, rats were treated with a single oral dose of 10 (female rats) or 100 mg CPA/kg body wt (male rats). Four DNA adducts were detected in the liver of both gender. In female rats, maximal total DNA adduct levels of 3.40 +/- 0.04 adducts/10(6) nucleotides were observed after 1 week. Eleven weeks later, 40% of the adducts determined after 1 week were still detectable. In male rats, maximal hepatic DNA adduct levels of approximately 98 +/- 3/10(9) nucleotides were attained after 2 weeks. The adduct level decreased during the following 4 weeks to approximately 40% of the earlier observed maximal level. To study the accumulation of the CPA-DNA adducts, rats were treated daily with a low oral dose of 50 micrograms CPA/kg body wt for 42 days. During this treatment period, the level of the four adducts increased continuously from approximately 10 to approximately 380 adducts/10(9) nucleotides in the liver of female rats. DNA adducts were formed at much lower levels in male rats; only one type of DNA adduct was detectable, the level of which increased to approximately 6 adducts/10(9) nucleotides after 42 days. In conclusion, CPA induces DNA adducts in rat liver; binding of the steroid is much higher in female compared to male rats. The CPA-DNA adducts show a high persistence and as a consequence of their long half life, CPA-DNA adducts accumulate significantly in the liver of rats.