THE DNA-DAMAGING DRUG CYPROTERONE-ACETATE CAUSES GENE-MUTATIONS AND INDUCES GLUTATHIONE-S-TRANSFERASE-P IN THE LIVER OF FEMALE BIG-BLUE(TM)TRANSGENIC F344 RATS

The gestagenic and antiandrogenic drug cyproterone acetate (CPA) is mi togenic, tumorigenic and induces DNA-adducts and DNA-repair synthesis in rat liver. Thus CPA is expected to be mutagenic, However in pike mu tagenicity test systems were negative, To examine whether CPA induces mutations in rat liver, the in vivo mutation assay based on Big Blue(T M) transgenic F334 rats was employed, Single oral doses of 25, 50, 75, 100 and 200 mg CPA/kg b.w. respectively were administered to female B ig Blue(TM) 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 o f (80 +/- 8) x 10(6) mutations. One-hundred and 75 mg CPA/kg b.w. resu lted in mutation frequencies of (35 +/- 5) and (27 +/- 5) x 10(-6), re spectively, The mutation frequency at doses of 50 and 25 mg CPA/kg b. cv. was similar to that of vehicle treated controls. Statistical analy sis of the dose-effect relationship revealed that it was not possible to decide whether a threshold dose exists or not, DNA adducts were ana lyzed by the P-32-postlabelling technique, The total level of the majo r and the two minor adducts observed in the autoradiograms increased b etween doses of 25 to 75 mg CPA/kg b.w. to a maximum of similar to 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 treat ment no preneoplastic liver foci mere observed, However, single glutat hione-S-transferase placental form (GST-P) positive hepatocytes were o bserved and the frequency was dependent on the dose. These cells are n ot supposed to represent initiated cells, since they occurred only tra nsiently after 6 weeks and disappeared thereafter completely. In concl usion, our results demonstrate that CPA is mutagenic in vivo. The muta tion frequency increased at high CPA doses, when the increase of the D NA adduct formation had already ceased. This suggests that the mitogen ic activity of CPA is required to express the mutations.