Transcriptional regulation of murine cytochrome P450 2a5 by glucocorticoids: Implications for nicotine metabolism

Larin, Meghan Elizabeth
Journal Title
Journal ISSN
Volume Title
University of Guelph

Cytochrome P450 2a5 (Cyp2a5), the mouse orthologue of human CYP2A6, catalyzes the metabolism of nicotine to cotinine. Several xenobiotics induce ' Cyp2a5' expression; however, the effect of glucocorticoids on Cyp2a5 expression and nicotine metabolism has not been investigated. Treatment of primary mouse hepatocytes with corticosterone and dexamethasone (DEX) induced ' Cyp2a5' and increased cotinine formation. RU486 did not abrogate ' Cyp2a5' induction by corticosterone; however, supramicromolar concentrations of RU alone and the pregnane X receptor (PXR) agonist pregnenolone-16[alpha]-carbonitrile induced 'Cyp2a5' mRNA expression, suggesting involvement of PXR. Reporter activity using a p2a5-3033+10luc reporter construct decreased in DEX-treated Hepa 1-6 cells and hepatocytes. Co-transfection with a PXR expression plasmid recovered some luciferase activity. Chromatin immunoprecipitation revealed that DEX may increase PXR binding at the proximal HNF4[alpha] response element. In summary, glucocorticoids appear to up-regulate Cyp2a5 via a mechanism involving PXR. Glucocorticoid-mediated induction of Cyp2a5 enhances nicotine metabolism, and may influence smoking cessation.

Cytochrome P450 2a5, nicotine metabolism, nicotine, cotinine, transcriptional regulation, glucocorticoids