In the present study, the time- and concentration-dependent effects of the carcinogen benzo[a]pyrene (BaP) on c-fos, c-jun, c-myc and c-Ha-ras expression were evaluated in primary cultured rat hepatocytes. These genes exhibited differential patterns of expression with peak mRNA levels at different times following incubation in the presence of serum mitogens. The expression of c-fos and c-jun was markedly inhibited by BaP (3 μM), with pronounced effects observed during the early part of the induction response. In contrast, the kinetics of c-myc and c-Ha-ras inducibility were enhanced by BaP (3 μM) leading to significant enhancement of mRNA levels. The gene modulatory effects of BaP were concentration dependent in the range of 0.3- 30 μM. Challenge with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (1 nM), an aryl hydrocarbon receptor (AhR) agonist, elicited responses comparable to BaP for c-jun and c-Ha-ras, but not for c-fos or c-myc. α-naphthoflavone (10 nM), antagonist/agonist of the AhR and inhibitor of cytochrome P450, elicited c-jun and c-Ha-ras responses comparable to BaP. Pretreatment of the cells with this agent nullified the modulatory effects of BaP on c-fos and c-myc. These results suggest that deregulation of growth-related gene expression in cultured rat hepatocytes by BaP is mediated by complex mechanisms that may involve AhR signalling and oxidative metabolism of the parent compound.
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