REGULATION AND BIOLOGICAL ROLE OF ETHANOL INDUCIBLE CYTOCHROME P450 2E1 (CYP2E1)

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We have demonstrated multiple regulatory mechanisms for CYP2E1: induction via transcription, mRNA stabilization, activation of mRNA translation and protein stabilization, suppression via transcription, mRNA degradations and protein degradation. We have recently reported transcriptional suppression of CYP2E1 gene by an exogenous compound, YH439. The potential beneficial effect of YH439 were studied in an in vivo model of acute hepatitis by treatment with carbon tetrachloride. In vivo hepatobiliary imaging analyses revealed that YH439 efficiently protects liver injury from carbon tetrachloride. These results were confirmed by the corresponding changes in the levels of serum transaminases and by histological evaluations. These data were recently published in Nucl. Med. Biol. Because of numerous recent reports about the role of enzymes involved in early signal transduction in cell death, activities of these enzymes in carbon tetrachloride-treated rat livers were measured. The level of c-jun kinase activity was transiently (1-2 hr) and selectively activated while p-38 protein kinase or mitogen activated protein kinase remained unchanged. Consistent with the in vivo data, we also observed that c-jun kinase in PC12 and COS-7 cells was selectively activated by 4-hydroxynonenal (HNE), another cytotoxic metabolite from the CYP2E1-mediated metabolism of long chain fatty acids. The selective c-jun activation was dependent upon HNE concentration and transient (within 15-30 min) upon HNE treatment, long before the apoptotic cell death. To further elucidate the relationship between the c-jun kinase activation and cell death in an in vitro model, we have recently transfected human CYP2E1 cDNA into HepG2 and Neuro2 cells via stable transfection. Using these cells with high level of CYP2E1 protein and activity as an in vitro model of cell death, we are testing the effects of various CYP2E1 substrates including ethanol, arachidonic acid and acetaminophen (Tylenol). In addition, changes in the level of DNA-adducts in the CYP2E1-transfected cells, upon treatment of CYP2E1 substrates, are being determined by HPLC.