Transcriptional inhibition of cytochrome P4502E1 by a synthetic compound, YH439.

The molecular mechanism of cytochrome P4502E1 (CYP2E1) inhibition by a synthetic compound, YH439, was studied. In rats treated with YH439, N-nitrosodimethylamine demethylase activity and the amount of immunoreactive CYP2E1 were rapidly decreased in time- and dose-dependent manners. Within 2 h after a single dose of YH439 (150 mg/kg), the CYP2E1-catalyzed activity in uninduced rats was decreased by about 30% and by 43% at 24 h after YH439 injection. YH439 treatment also reduced the elevation of CYP2E1 enzyme activity in starved (induced) animals by 34%. More profound inhibition of CYP2E1 protein levels was observed by immunoblot analysis. The level of CYP2E1 catalytic activity and immunoreactive protein remained suppressed for at least 48 h and returned to normal level at 72 h after YH439 treatment. The levels of immunoreactive CYP2B1/2 protein and catalytic activity were moderately increased while little change was observed in the levels of NADPH-dependent P450 oxidoreductase activity and its protein after treatment with YH439. Unlike competitive inhibitors of CYP2E1, YH439 rapidly (within 2 h) decreased the level of CYP2E1 mRNA, while malotilate, a structural analog of YH439, slightly suppressed its level. Nuclear run-on transcription analyses at 2, 4, and 8 h post-YH439 administration revealed that the inhibition of CYP2E1 by YH439 is at the level of transcription, indicating that YH439 is a new class of CYP2E1 inhibitor. Our data demonstrate that YH439 is a powerful inhibitor of CYP2E1 expression and is thus potentially useful as a pharmacological tool to study CYP2E1 function as well as a potential therapeutic agent.