Dose dependent induction of DNA adducts, gene mutations, and cell proliferation by the antiandrogenic drug cyproterone acetate in rat liver.
1. CPA does not only induce the formation of DNA adducts but also of mutations in female rat liver. 2. The mutation frequency exhibited a characteristic time course. Within a period of 3 days post administration, a tremendous increase was noted, which remained at a high level until 2 weeks post exposure. Thereafter, most mutation-carrying cells were eliminated within a period of 2 weeks leaving a cell population remaining at a constant level for another 4 weeks. Thus, the length of the observation period post exposure, i. e. the manifestation time, seems to be a critical factor for the strength of the mutagenic response. The highest as observed between 1 and 2 weeks post exposure. Correspondingly, the dose response curve recorded 2 weeks post exposure showed a higher mutagenic response than the curve after 6 weeks of exposure recorded previously. 3. When CPA-induced mutations were recorded as a function of the dose, mutation frequencies at the lower dose range were found that did not differ from those of controls. The non-effective dose recorded 2 weeks post exposure was much lower than that recorded after 6 weeks of exposure indicating that it is a function of the manifestation time. Since DNA adducts were formed in high amounts at the non-effective doses, we assume that the mitogenic activity required for the conversion of DNA adducts into mutations was not sufficiently strong. The liver of adult animals exhibits a very low endogeneous proliferation rate, which is not likely to contribute significantly to the expression of mutations. We conclude that it is the mitogenic activity of CPA itself, which stimulates the expression of mutations.
Wolff
T
T
GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Toxikologie, Neuherberg, Gernany.
Topinka
J
J
Deml
E
E
Oesterle
D
D
Schwarz
L R
LR
D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001426:Bacterial Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D017373:Cyproterone Acetate / Q000737:chemistry / Q000494:pharmacology*; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins; D005260:Female; D056968:Lac Repressors; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics; D013997:Time Factors
D000726:Androgen Antagonists; D001426:Bacterial Proteins; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D009153:Mutagens; D012097:Repressor Proteins; D017373:Cyproterone Acetate