REGULATION OF ETHANOL-INDUCIBLE CYTOCHROME P450 GENE

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We previously cloned and demonstrated four distinct types of regulation of P450llE1. During the past year, we demonstrated two additional mechanisms of P450llE1 regulation: translational activation of P45OllE1 by isoniazid and pyrazine; and pretranslational suppression of hepatic P45OllE1 during pregnancy. Specific translational induction of P45OllE1 by isoniazid and pyrazine was demonstrated. However, pyridazine and pyrimidine, two stereoisomers of pyrazine, did not activate P45OllE1, indicating a more inflexible structural requirement for P450llE1 mRNA translation into its protein. In contrast, pyrrole with five-membered ring structure reduced P45OllE1 activity resulting from rapid reversal (within 1 day) upon parturition were also demonstrated. Exogenously administered steroids (progesterone, estrogen, and thyroxine) and peptide growth factors (placental lactogen, prolactin, and growth hormone) did not cause significant changes in P45OllE1 level. The changes in P45OllE1 was only observed in liver but not in extrahepatic tissues, suggesting a potential role of hepatocyte growth factor in P45OllE1 regulation. In collaboration with Dr. Ravindranath, the presence of P45OllE1 in brain and its induction after chronic ethanol drinking were demonstrated. We also showed that P45OllE1 can be phosphorylated by protein kinase C, cAMP dependent protein kinase or calmodulin-dependent protein kinase.