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 (P450IIE1) of both rat and human. We have also demonstrated three distinct types of regulation of P450IIE1 in rat. The three types of upregulation of P450IIE appeared to be present in liver, lung and kidney tissues. The molecular mechanism of P450IIE1 regulation by other exogenous regulators and during pregnancy were further investigated. Pretranlational activation of P450IIE1 during ketosis induced by a fat diet where the elevation of its mRNA level correlated with the levels of acetoacetate and beta-hydroxybutyrate but not with that of acetone which activates P450IIE1 without elevating its mRNA level. Specific translational induction of P450IIE1 by isoniazid and N-heterocyclic compounds such as pyrazine was demonstrated. Pretranslational reduction of P450IIE during pregnancy and rapid reversal upon parturition were studied. The reduction of P450IIE1 during late-term pregnancy indicates a negative hormonal control mechanism which we are currently investigating. In contrast, pentoxyresorufin O-depentylase (associated with P450IIB1/B2) was pretranslationally activated by the same inducer, pyridine. A rapid and sensitive assay for P450IIE1 is being developed for the detection of P450IIE1 expressed in human lymphocytes.