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

• Published in: Carcinogenesis (New York) 1995-10, Vol.16 (10), p.2369-2372
• Main Authors: Werner, S., Toplnka, J., Wolff, T., Schwarz, L.R.
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - metabolism; Animals; Autoradiography; Biological and medical sciences; Cells, Cultured; Cyproterone Acetate - metabolism; DNA Adducts - isolation & purification; DNA Adducts - metabolism; Drug toxicity and drugs side effects treatment; Female; Kinetics; Liver - metabolism; Male; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Pharmacology. Drug treatments; Phosphorus Radioisotopes; Rats; Rats, Wistar; Time Factors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/16.10.2369

Cyproterone acetate (CPA) is a synthetic steroid which is widely used in antlandrogenic 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 32 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/106 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 ∼98±3/109 nucleotides were attained after 2 weeks. The adduct level decreased during the following 4 weeks to ∼9;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 μg CPA/kg body wt for 42 days. During this treatment period, the level of the four adducts increased continuously from ∼10 to ∼380 adducts/109 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 ∼6 adducts/10 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.