No-effect level in the mutagenic activity of the drug cyproterone acetate in rat liver. Part I. Single dose treatment.

Abstract

The anti-androgen and progestagen cyproterone acetate (CPA) is known to cause liver tumors in rats. The drug has been identified recently as a mutagen in the liver of female transgenic lambdalacI (Big Blue) rats at high doses after an expression time of 6 weeks. A dose of 50 mg CPA/kg BW, however, did not increase the mutation frequency (MF) of controls indicating a no-effect level of mutagenicity [Carcinogenesis 19 (1998) 241]. The present study was performed to assess the existence of a no-effect level of mutagenicity. In order to figure out conditions of maximum response, the time course of the MF was determined after administration of a single dose of 100 mg CPA/kg BW to female Big Blue rats. The MF showed a strong initial rise to a maximum 2 weeks after CPA administration accompanied by a corresponding increase of cell proliferation and of DNA adduct levels. Thereafter, the MF decreased within further 2 weeks to one third of the maximum level which was maintained for another 4 weeks. The DNA adduct levels decreased only by 15% during this time period suggesting that mutated hepatocytes were eliminated predominantly. A dose dependence curve determined at a fixation time of 2 weeks revealed a no-effect level of 5 mg CPA/kg BW for mutagenicity. In conclusion, our findings indicate that the length of the observation period may be a critical determinant for the outcome of a mutagenesis study in rat liver. Furthermore, the existence of a no-effect level for the mutagenicity of CPA in rat liver was confirmed. However, it has to be clarified whether the dose of 5 mg CPA/kg BW corresponding to the "transient" type of mutations or the previous dose of 50 mg CPA/kg BW related to a "permanent" type of mutations is more relevant for the assessment of the genotoxic risk.

• Authors: Jan Topinka, Doris Oesterle, Roland Reimann, Thomas Wolff
• Journal: Mutation research (Mutat Res) Vol. 550 Issue 1-2 Pg. 89-99 (Jun 04 2004) ISSN: 0027-5107 [Print] Netherlands
• PMID: 15135643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA Adducts
• Mutagens
• Cyproterone Acetate

Topics

• Animals
• Animals, Genetically Modified
• Antineoplastic Agents (administration & dosage)
• Apoptosis
• Cell Division
• Cyproterone Acetate (administration & dosage)
• DNA Adducts
• Dose-Response Relationship, Drug
• Female
• Liver (drug effects)
• Mutagens
• Mutation
• Rats
• Rats, Inbred F344
• Time Factors