No-effect level in the mutagenic activity of the drug cyproterone acetate in rat liver. Part I. Single dose treatment.
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.
Topinka
Jan
J
Institute of Toxicology, GSF-National Center of Environment and Health, D-85764 Neuherberg, Germany. topinka@gsf.de
Oesterle
Doris
D
Reimann
Roland
R
Wolff
Thomas
T
D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D002455:Cell Division; D017373:Cyproterone Acetate / Q000008:administration & dosage*; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects*; D009153:Mutagens; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009153:Mutagens; D017373:Cyproterone Acetate