Formation of DNA-adducts by selected sex steroids in rat liver

Abstract

<jats:p> 1 We are reporting investigations into the potential of the steroid hormones chlormadinone acetate (CMA), cyproterone acetate (CPA), ethinylestradiol (EE<jats:sub>2</jats:sub>) gestodene (GEST), megestrol acetate (MGA), norethis terone acetate (NET-Ac), estradiol (E<jats:sub> 2</jats:sub>), and progester one (P) to form DNA-adducts in rat liver in vivo. </jats:p><jats:p> 2 Compound-related DNA-adduct spots were detected in male and female rat liver following CMA, CPA, and MGA using the <jats:sup>32</jats:sup>P-postlabeling-technique. Substance- specific DNA-adducts were also observed in male rats after administration of E<jats:sub>2</jats:sub>. The other compounds showed no DNA-adduct formation. After treatment with CMA, CPA or MGA, the relative adduct labeling (RAL) differed sex- and substance-specifically. </jats:p>

Antigenotoxic effect of nordihydroguaiaretic acid against chlormadinone acetate-induced genotoxicity in mice bone-marrow cells

“…CMA produces mammary tumors in dogs [32] and increases the incidence of mammary gland hyperplasia and mammary nodules [33]. It forms DNA adducts in rat and human hepatocytes in vitro [34][35][36] and also induces micronuclei in rat liver cells in vivo [20]. Antioxidants are known to reduce mutagenic potential of various mutagens in in vivo studies [37,38].…”

Untitled

“…This view is supported by the findings with two structural analogues of cyproterone acetate, chlormadinone acetate (CMA) and megestrol acetate (MGA) which also contain the 6,7-double bond. Both progestins were found to induce DNA adducts and unscheduled DNA synthesis in female rat and in human liver cells (Feser et al 1996;Martelli et al 1996b;Topinka et al 1995). In contrast, other sex steroids not possessing the 6,7-double bond, like gestodene, norethisterone acetate or the natural cyproterone acetate MiniReview analogue progesterone, were not able to form DNA adducts Feser et al 1996).…”

“…Horizontal arrows illustrate onset of various effects, vertical arrows amount of DNA adduct formation. a data from Werner et al (1995); b data from Topinka et al (1993); c data from Feser et al (1996); d data from Schulte-Hermann et al (1980); e data from Kasper & Mueller (1996); f data from Krebs et al (1998); g data from Martelli et al (1996a); h data from Deml et al (1993); i data from Schuppler & Günzel (1979).…”

Cyproterone Acetate: A Genotoxic Carcinogen?

“…Both progestins were found to induce DNA adducts and unscheduled DNA synthesis in female rat and in human liver cells Martelli et al 1996b;Topinka et al 1995). In contrast, other sex steroids not possessing the 6,7-double bond, like gestodene, norethisterone acetate or the natural cyproterone acetate MiniReview analogue progesterone, were not able to form DNA adducts Feser et al 1996).…”

“…Horizontal arrows illustrate onset of various effects, vertical arrows amount of DNA adduct formation. a data from Werner et al (1995); b data from Topinka et al (1993); c data from Feser et al (1996); d data from Schulte-Hermann et al (1980); e data from Kasper & Mueller (1996); f data from Krebs et al (1998); g data from Martelli et al (1996a); h data from Deml et al (1993); i data from Schuppler & Günzel (1979). ic carcinogen generally implies that no safe dose can be defined since genotoxins, and among them in particular those which induce DNA adducts are assumed to operate by a non-thresholded mode of action. According to this view the quantitative differences in the dose-response relationship merely reflect differences in the detection limits of the various endpoints, e.g.…”