Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate or megestrol acetate

The synthetic anti-androgen and progestin cyproteroneacetate (CPA), recently found to be genotoxic for the liver,and two structurally similar progestins, chlormadinoneacetate (CMA) and megestrol acetate (MGA), have beencompared for clastogenic and tumor-initiating activities infemale rats. In the micronucleus assay, carried out in ratsgiven a single p.o. dose of 100 mg/kg, CPA induced themaximum increase in the frequency of micronucleatedhepatocytes (6.6-fold as compared to controls) when treat-ment was performed 3 days before partial hepatectomyand cell sampling 2 days later. Under the same experimentalconditions the clastogenic potencies of CMA and MGAwere 69% and 36% of that of CPA respectively. In theliver foci assay, p.o. dosing with 100 mg/kg CPA once aweek for 6 successive weeks induced, as compared tocontrols, a significant increase in the number and area ofy-glutamyltranspeptidase-positive foci. At the same dosageschedule the tumor-initiating activity of CMA and MGAwas 7- to 10-fold lower than that of CPA. These findingssuggest that the 1,2 a-methylene group, present in CPAbut absent in both CMA and MGA, favours the activationto a reactive species and/or hinders the biotransformationto non-toxic metabolites.IntroductionCyproterone acetate (CPA*), a widely used synthetic steroidwith both anti-androgenic and progestational activity, wasfound to increase the incidence of hepatic tumors in rats (1).Subsequent studies suggested that this effect was most likelyattributable to tumor-promoting activity (2-4), and this inter-pretation was favoured by the lack of activity in mutagenicityassays (5). However, in the last few years the followingevidence has been given that CPA also has genotoxic activity:it has been shown to form DNA adducts in primary culturesof rat hepatocytes and in the rat liver (6), to elicit DNA repairsynthesis in primary hepatocytes from female rats (7), and toinduce enzyme-altered foci in the liver of female rats, whenadministered during the initiation phase (8). More recentlyCPA has been found to induce DNA repair synthesis in primarycultures of hepatocytes from both male and female humandonors (9). To acquire further information about CPA geno-toxicity and to compare its effect with that of structurallyrelated progestins we examined in this study the clastogenic