Transcriptional regulation of mouse hepatic cytochrome P450 2A5 gene expression

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Leclair, Andrea Valerie
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University of Guelph

Induction of mouse cytochrome P450 2A5 (CYP2A5) during hepatotoxicity is related to altered cellular redox, however the molecular mechanism is not known. Expression of CYP2A5 is induced by phenobarbital by a transcriptional mechanism. This study investigated the transcriptional regulation of CYP2A5 expression by altered cellular redox and phenobarbital. Alteration of cellular redox by DTTox, menadione, nitrofurantoin, and 't'-butylhydroperoxide increased 'Cyp2a5' promoter activity, however not to the extent that CYP2A5 mRNA expression was increased during altered cellular redox, indicating that post-transcriptional mechanisms may also be involved. Increased ' Cyp2a5' promoter activity following phenobarbital treatment correlated well with increased CYP2A5 mRNA expression. The 'Cyp2a5' promoter region was not transactivated by mCAR and mutation of the putative CAR/PXR half-site did not affect promoter activity. The CAR antagonist androstenol did not inhibit 'Cyp2a5' promoter activity. The phenobarbital-mediated increase in activity of the proximal 3 kb region of the 'Cyp2a5' promoter is not dependent on CAR.

induction, mouse cytochrome P450 2A5, hepatotoxicity, altered cellular redox, phenobarbital, transcriptional regulation