Comparative study of DNA repair induced by cyproterone acetate, chlormadinone acetate and megestrol acetate in primary cultures of human and rat hepatocytes.
Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50 microM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats. These results, which agree with previous findings, suggest that for these sex steroids extrapolation to humans of results obtained in rats might be questionable.
Martelli
A
A
Institute of Pharmacology, University of Genoa, Italy.
Mattioli
F
F
Ghia
M
M
Mereto
E
E
Brambilla
G
G
D000818:Animals; D002478:Cells, Cultured; D002715:Chlormadinone Acetate / Q000633:toxicity*; D017373:Cyproterone Acetate / Q000633:toxicity*; D004260:DNA Repair / Q000187:drug effects*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008535:Megestrol / Q000031:analogs & derivatives* / Q000633:toxicity; D019290:Megestrol Acetate; D045167:Progesterone Congeners / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D045167:Progesterone Congeners; D002715:Chlormadinone Acetate; D017373:Cyproterone Acetate; D008535:Megestrol; D019290:Megestrol Acetate