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Metabolic activation of 2-acetylaminofluorene is required for induction of multidrug resistance gene expression in rat liver cells
Institute of Toxicology, University of Tübingen, D-72074 Tübingen Germany
2MRC Toxicology Unit, Leicester, UK
3Laboratory of Experimental Carcinogenesis National Cancer Institute, National Institutes of Health Bethesda, MD 20892
4Food and Drug Administration HFD-530, Rockville, MD 20857, USA
1To whom correspondence should be addressed
P-Glycoprotein the multidrug resistance (mdr) efflux transporter is encoded by class 1 mdr genes (mdrl) in humans and rodent species. In rat liver and in rat hepatocytes in primary culture, expression of mdrl genes can be induced with the carcinogenic aromatic amine 2-acetylaminofluorene (2-AAF). As a consequence, increased P-glyco protein levels led to an accelerated efflux of vinblastine from the hepatocytes and to resistance towards vinblastine mediated cytotoxicity. N-Hydroxylation, an obligatory initial step in the activation of 2-AAF into electrophilic DNA-binding metabolites is catalyzed predominantly by cytochrome P450 (CYP)1A2, an isozyme present in normal rat liver. In rat hepatocytes in primary culture, mdrl induction with 2-AAF could be inhibited by addition of the CYP1A-inhibitor 
-naphthoflavone, indicating the requirement for metabolic conversion of 2-AAF to act as an inducer of mdrl gene expression. Both N-hydroxy-2- AAF and the mutagenic 2-AAF derivative N-acetoxy-2- AAF (AAAF) were more potent than 2-AAF as mdrl inducers. mdrl induction also decreased when deacetylation of AAAF, which strongly accelerates its conversion into a mutagen, was inhibited with paraoxon. Furthermore, rat liver epithelial cells stably transfected with mouse CYP1A2 showed inducibillty of mdrl gene expression with 2 whereas the parental cell line, which is devoid of CYP1A2 activity, did not. These findings indicate that electrophilic metabolites formed during 2-AAF or AAAF metabolism are responsible for mdrl induction in rat hepatocytes. The Increased mdrl gene expression may reflect an adaptive cellular response to electrophiles which includes enhanced synthesis of P-glycoprotein aimed to protect the cell from further damage.
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