negative growth stimuli or in their vulnerability to acquiring Switzerland mutations. In rodents, the liver was found to be particularly 2 To whom correspondence should be addressed sensitive towards non-genotoxic carcinogens (5). Therefore, Down-regulation of the mitogenic activity of the rodent liver we addressed the question whether cultured rat hepatocytes, carcinogen cyproterone acetate (CPA) and of epidermal stimulated by an exogenous or an endogenous mitogen, respond growth factor (EGF)

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... ere compared in cultured rat differentially to negative growth control initiated by transhepatocytes. Both hepatomitogens produce an increase in forming growth factor β1 (TGF-β1*). This was carried out the expression of proliferating cell nuclear antigen (PCNA) with two rodent liver mitogens, the carcinogenic and synthetic and in [ 3 H]thymidine incorporation in a dose-dependent steroid cyproterone acetate (CPA) and the endogenous peptide manner. In combination, the two mitogens induced an epidermal growth factor (EGF). additive mitogenic response. Concomitant exposure to the CPA is found in oral anti-acnegenic contraceptives and is growth inhibitory cytokine transforming growth factor β1 used to treat prostate carcinoma, male hypersexualism and (TGF-β1) resulted in a differential dose-dependent downsigns of androgenization in women. In a rat liver foci bioassay, regulation of PCNA-expressing cells. The correspond-CPA induced altered foci in female rats (6) but not in male ing down-regulation of CPA-induced PCNA expression rats (7) . At lower doses CPA increased benign liver proliferation required a 3-to 5-fold higher TGF-β1 concentration than (8) and at higher levels hepatic tumours in rats and mice, both for EGF-induced expression. In contrast, CPA-exposed males and females (9). The mitogenic activity of CPA in rat hepatocytes become vulnerable to and EGF-exposed cells liver was demonstrated in vivo (10) and in vitro (11) , whereas protected against the apoptosis-inducing activity of TGFin human hepatocytes the mitotic activity was found only in β1 (Ͼ0.