Carcinogenesis, Vol 19, 241-245, Copyright © 1998 by Oxford University Press
O Krebs, B Schafer, T Wolff, D Oesterle, E Deml, M Sund and J Favor
The gestagenic and antiandrogenic drug cyproterone acetate (CPA) is
mitogenic, tumorigenic and induces DNA-adducts and DNA-repair synthesis in
rat liver. Thus CPA is expected to be mutagenic. However in vitro
mutagenicity test systems were negative. To examine whether CPA induces
mutations in rat liver, the in vivo mutation assay based on Big Blue
transgenic F344 rats was employed. Single oral doses of 25, 50, 75, 100 and
200 mg CPA/kg b.w. respectively were administered to female Big Blue rats.
Six weeks after treatment, liver DNA was assayed for mutations. At the
highest dose, 200 mg CPA/kg b.w., the frequency of (17 +/- 4) x 10(-6)
spontaneous mutations was increased to a maximum of (80 +/- 8) x 10(-6)
mutations. One-hundred and 75 mg CPA/kg b.w. resulted in mutation
frequencies of (35 +/- 5) and (27 +/- 5) x 10(-6), respectively. The
mutation frequency at doses of 50 and 25 mg CPA/kg b.w. was similar to that
of vehicle treated controls. Statistical analysis of the dose-effect
relationship revealed that it was not possible to decide whether a
threshold dose exists or not. DNA adducts were analyzed by the
32P-postlabelling technique. The total level of the major and the two minor
adducts observed in the autoradiograms increased between doses of 25 to 75
mg CPA/kg b.w. to a maximum of approximately 12,000 +/- 3000 adducts per
10(9) nucleotides. The level did not further increase significantly with
100 and 200 mg CPA/kg b.w. After CPA treatment no preneoplastic liver foci
were observed. However, single glutathione-S-transferase placental form
(GST-P) positive hepatocytes were observed and the frequency was dependent
on the dose. These cells are not supposed to represent initiated cells,
since they occurred only transiently after 6 weeks and disappeared
thereafter completely. In conclusion, our results demonstrate that CPA is
mutagenic in vivo. The mutation frequency increased at high CPA doses, when
the increase of the DNA adduct formation had already ceased. This suggests
that the mitogenic activity of CPA is required to express the mutations.
ARTICLES
The DNA damaging drug cyproterone acetate causes gene mutations and induces glutathione-S-transferase P in the liver of female Big Blue transgenic F344 rats [published erratum appears in Carcinogenesis 1998 Apr;19(4):707]
Institute of Molecular Animal Breeding, Gene Center, Ludwig-Maximilians- Universitat, Munchen, Germany. Krebs@lmb.uni-muenchen.de
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