| Autor: |
Schrenk, Dieter, Gant, Timothy W., Michalke, Alfred, Orzechowski, Achim, Silverman, Jeffrey A., Battula, Narayana, Thorgeirsson, Snorri S. |
| Zdroj: |
Carcinogenesis; 1994, Vol. 15 Issue 11, p2541-2546, 6p |
| Abstrakt: |
P-Glycoprotein the multidrug resistance (mdr) efflux transporter is encoded by class 1 mdr genes () in humans and rodent species. In rat liver and in rat hepatocytes in primary culture, expression of 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. -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, induction with 2-AAF could be inhibited by addition of the CYP1A-inhibitor α-naphthoflavone, indicating the requirement for metabolic conversion of 2-AAF to act as an inducer of gene expression. Both -hydroxy-2- AAF and the mutagenic 2-AAF derivative -acetoxy-2- AAF (AAAF) were more potent than 2-AAF as inducers. 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 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 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. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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