Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line

Several cytochrome P450 (CYP) enzymes are expressed in the human lung, wher e they participate in metabolic inactivation and activation of numerous exo genous and endogenous compounds. In this study, the expression pattern of a ll known xenobiotic-metabolizing CYP genes was characterized in the human a lveolar type II cell-derived A549 adenocarcinoma cell line using qualitativ e reverse transcriptase/polymerase chain reaction (RT-PCR). In addition, th e mechanisms of induction by chemicals of members in the CYP1 and CYP3A sub families were assessed by quantitative RT-PCR. The expression of messenger RNAs (mRNAs) of CYPs 1A1, 1B1, 2B6, 2C, 2E1, 3A5, and 3A7 was detected in t he A549 cells. The amounts of mRNAs of CYPs 1A2, 2A6, 2A7, 2A13, 2F1, 3A4, and 4B1 were below the limit of detection. 2,3,7,8-tetrachlorodibenzo-p-dio xin (TCDD) induced CYP1A1 and CYP1B1 mRNAs 56-fold and 2.5-fold, respective ly. CYP3A5 was induced 8-fold by dexamethasone and 11-fold by phenobarbital . CYP3A4 was not induced by any of the typical CYP3A4 inducers used. The ty rosine kinase inhibitor genistein and the protein kinase C inhibitor stauro sporine blocked TCDD-elicited induction of CYP1A1, but they did not affect CYP1B1 induction. Protein phosphatase inhibitors okadaic acid and calyculin A enhanced TCDD-induction of CYP1B1 slightly, but had negligible effects o n CYP1A1 induction. These results suggest that CYP1A1 and CYP1B1 rue differ entially regulated in human pulmonary epithelial cells and give the first i ndication of the induction of CYP3A5 by glucocorticoids in human lung cells . These results establish that having retained several characteristics of h uman lung epithelial cell CYP expression, the A549 lung cell line is a valu able model for mechanistic studies on induction of the pulmonary CYP system .