ETHANOL-INDUCIBLE CYTOCHROME P4502E1 - GENETIC-POLYMORPHISM, REGULATION, AND POSSIBLE ROLE IN THE ETIOLOGY OF ALCOHOL-INDUCED LIVER-DISEASE

In the Tsukamoto-French model, ethanol causes an important 10-20-fold induction of ethanol-inducible cytochrome P4502E1 (CYP2E1), mediated t hrough enzyme stabilization and increased rate of gene transcription. The CYP2E1 induction results in a pronounced increase in the rate of N ADPH-dependent microsomal lipid peroxidation, an elevation which is no t seen after simultaneous administration of the CYP2E1 inhibitor diall ylsulfide. Increased amounts of lipid peroxides are seen in plasma and red blood cells of both rats and humans during high ethanol intake. A mechanism for ethanol-dependent liver damage is proposed which involv es the CYP2E1-dependent lipid peroxide formation, either directly by i ts capability to induce NADPH-dependent peroxidation in the microsomal membranes or indirectly by a hypoxia-mediated transformation of xanth ine dehydrogenase to xanthine oxidase, in activation of Ito cells and Kupffer cells to yield cytokine and collagen production. The CYP2E1 ge ne is polymorphic among Caucasians. Four different unrelated or partia lly linked polymorphisms have been observed. One polymorphism in the 5 '-flanking region has been described to be associated with altered enz yme expression in vitro, and the rare allele was found to be less freq uent among Swedish patients having lung cancer when compared to two di fferent control groups. Another polymorphism, detectable with Dra I re striction endonuclease fragment length polymorphism (RFLP), was locali zed to intron 6, and the rare allele was less common among Italian alc oholics with clinical signs of liver cirrhosis, as compared to control s. Several other mutations in the CYP2E1 gene were found to be associa ted with this allele. However, further research is needed to relate th e CYP2E1 gene polymorphism with incidence of liver cirrhosis.