Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells

Abstract

It was shown recently that in epithelial Caco-2 cells the food contaminant benzo[ a]pyrene (B[ a]P) is metabolized and B[ a]P-sulfate metabolites were transported out of the cells. The aim of this study was to investigate whether B[ a]P and other polycyclic aromatic hydrocarbons (PAH) such as chrysene, phenanthrene, benzo[ k]fluoranthene (B[ k]F), dibenzo[ a,l]pyrene (DB[ a,l]P), and pyrene alone or in a mixture in a ratio as they occur in tobacco smoke have effects on gene expression of intestinal cytochrome P450 enzymes (CYP), Phase II enzymes and ATP-binding cassette (ABC)-transport proteins in the human Caco-2 cells. B[ a]P induced its own metabolism. Treatment of the Caco-2 cells with B[ a]P, chrysene, B[ k]F, or DB[ a,l]P induced mRNA expression of CYP1A1 and CYP1B1 specifically as measured by RT-PCR. In contrast, the mRNA expression of the microsomal epoxide hydrolase (mEH) was not affected by PAH. The gene expression of the Phase II enzymes UDP-glucuronosyltransferase 1A6 (UGT1A6) and UGT1A7 was also induced by these PAH but treatment with them had no effect on gene expression of sulfotransferases (SULT) at all. Of the ABC-transport proteins, MDR1 mRNA expression was induced by treatment with carcinogenic PAH, whereas MRP2 mRNA expression was not changed. The mixture of PAH also induced CYP1A1, CYP1B1, UGT1A6, and UGT1A7 mRNA expression. We conclude that B[ a]P, chrysene, B[ k]F, and DB[ a,l]P have specific effects on intestinal CYP1A1, CYP1B1, UGT1A6, and UDP1A7 mRNA expression but no effects on the expression of SULT.