No-effect level in the mutagenic activity of the drug cyproterone acetate in rat liver. Part II. Multiple dose treatment.
In order to probe for the existence of a no-effect levels for mutations induced by multiple dose treatment with cyproterone acetate (CPA), female lacI-transgenic Big Blue rats were treated daily for 3 weeks with oral doses of 5.0, 1.0 or 0.2mg/kg CPA b.w., respectively. The dose of 5mg/kg CPA b.w. ineffective as a single dose (see part I) increased the mutation frequency by 2.5-fold. Daily treatment with 1.0 and with 0.2 mg/kg CPA b.w. for 3 weeks, however, was not effective indicating that the 1 mg dose represents a no-effect level for multiple dose treatment. The finding that a total dose of 21 x 5 = 105 mg/kg CPA b.w. caused 50% less DNA adducts, but a mutation frequency three-fold higher (data extrapolated from part I) than observed after daily treatment with 5mg/kg CPA b.w. for 21 days points to a crucial role of cell proliferation in mutagenesis by CPA. Our present results, in combination with previous findings, offer a basis to estimate the risk to develop mutations in human liver following treatment with CPA. Previous studies revealed that CPA-DNA adducts are formed in human hepatocytes at lower levels than in those of female rats [Mutat. Res. 395 (1997) 179; Cancer Res. 56 (1996) 4391]. Moreover, an in vitro-study indicated that human hepatocytes in culture do not respond to the mitogenic effect of CPA, while rat hepatocytes did [Cancer Res. 51 (1991) 1143]. We conclude that the risk of humans to develop mutations under treatment with CPA is substantially lower than in the female rat.
Topinka
Jan
J
GSF-National Center of Environment and Health, Institute of Toxicology, Ingolstädter Landstrasse 1, 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; D016196:S Phase; D013997:Time Factors
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009153:Mutagens; D017373:Cyproterone Acetate