REGULATION OF ETHANOL-INDUCIBLE CYTOCHROME P450 GENE

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As a continuous ongoing project, the molecular regulatory mechanism of P450IIE was further investigated. We have previously identified and determined the structures of the ethanol-inducible cytochrome P450 (P450IIE) of both rat and human. We have also demonstrated three distinct types of regulation of P450IIE. The mechanism of P450IIE mRNA stabilization was further studied to identify intermediary metabolites responsible for the mRNA stabilization. The level of two ketone bodies (~-hydroxybutyrate and acetoacetate) positively correlated with the elevated level of P450IIE mRNA. In addition, the molecular mechanism of P450IIE reduction by CCl4, was also examined. Aniline hydroxylase and the amounts of immunoreactive P450IIE were rapidly decreased in a time-dependent manner after CCl4 injection. These declines were not accompanied by the changes in the level of P450IIE mRNA and transcriptional activity, indicating a post-translational inhibition by CCl probably due to specific destruction of P450IIE by locally generated free radical metabolites. In contrast, the amounts of immunoreactive other P450s such as P450IA and P450IIC did not appear to be affected by CCl4, indicating a specific destruction of P450IIE by its substrate. A method for the measurement of P450IIE in easily obtainable human tissues was also established. P450IIE1 expressed in cultured lymphocytes could be easily detected by specific antibody to P450IIE. The induction of lymphocyte P450IIE was observed in both human and rat lymphocytes. The levels of P450IIE in lymphocytes from alcoholic patients at admission and discharge are being studied.