Initiation of enzyme-altered foci by the synthetic steroid cyproterone acetate in rat liver foci bioassay

Abstract

Cyproterone acetate (CPA) is a synthetic steroid which is used in oral contraceptive and anti-androgen formulations. It has previously been classified as a tumor promoter in rat liver. Recent studies have shown that CPA induces DNA repair synthesis in isolated hepatocytes, and this implies that CPA is genotoxic. We studied the initiating activity of CPA in vivo by means of a rat liver foci bioassay, using weanling female Sprague-Dawley rats. The results show that CPA induces adenosine-triphosphatase-deficient and gamma-glutamyltranspeptidase-positive putative preneoplastic foci in a dose-dependent manner. This indicates that CPA has not only promoting but also initiating activity and may therefore act as a complete carcinogen in rat liver.

In vivo cell lineage analysis in cyproterone acetate-treated rat liver using genetic labeling of hepatocytes

“…CPA is now considered a complete carcinogen with both initiating and promoting activities. [16][17][18][19] The promoting activity of CPA is believed to be related to its mitogenic activity, 7,11,37 although contradictory results have been obtained. 38 Along the same lines, previous studies failed to show the initiating activity of CPA.…”

“…10 However, a number of more recent studies have documented the ability of CPA to cause DNA damage and hence induce the appearance of GSTp foci in the liver. 16,39 In this study, we sought to determine if the initiating activity of CPA was targeted to the same hepatocyte population as that which was sensitive to the mitogenic effect. The use of 2-AAF allowed us to amplify potentially initiated hepatocytes into preneoplastic foci that were detected using GSTp, a well-recognized marker of preneoplastic foci.…”

“…15 Subsequently, it was shown that CPA was genotoxic in various assays and could initiate enzyme-altered foci in the liver. [16][17][18][19] Therefore, it seems that CPA may act as a complete carcinogen in the rat liver. However, the actual relationship between mitogenic activity and initiating activity has yet to be established.…”

Long term phenobarbital administration does not promote the multiplication of hepatocytes replicating after single cyproterone acetate administration

“…It was subsequently demonstrated that CPA was also genotoxic (Deml et al, 1993;Krebs et al, 1998;Neumann et al, 1992) and it was suggested that CPA was a complete carcinogen, and that its promoter activity was linked to its mitogenic activity when administered for long period of time (Krebs et al, 1998). However, the relationship between genotoxic and mitogenic activity of CPA after acute administration were less clear.…”

“…It was then proposed that CPA behaved as a tumor promoter, capable of promoting the growth of initiated cells via its mitogenic activity, but devoid of tumor-initiating activity (Schulte-Hermann et al, 1980;Schulte-Hermann et al, 1983a;Schuppler et al, 1983). However, it was subsequently demonstrated that CPA was genotoxic in vivo and in cultured hepatocytes and could initiate preneoplastic lesions in the liver (Deml et al, 1993;Martelli et al, 1995;Neumann et al, 1992). Therefore CPA is now considered as a complete carcinogen.…”