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 through enzyme stabilization and increased rate of gene transcription. The CYP2E1 induction results in a pronounced increase in the rate of NADPH-dependent microsomal lipid peroxidation, an elevation which is not seen after simultaneous administration of the CYP2E1 inhibitor diallylsulfide. 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 involves the CYP2E1-dependent lipid peroxide formation, either directly by its capability to induce NADPH-dependent peroxidation in the microsomal membranes or indirectly by a hypoxia-mediated transformation of xanthine dehydrogenase to xanthine oxidase, in activation of Ito cells and Kupffer cells to yield cytokine and collagen production. The CYP2E1 gene is polymorphic among Caucasians. Four different unrelated or partially linked polymorphisms have been observed. One polymorphism in the 5'-flanking region has been described to be associated with altered enzyme expression in vitro, and the rare allele was found to be less frequent among Swedish patients having lung cancer when compared to two different control groups. Another polymorphism, detectable with Dra I restriction endonuclease fragment length polymorphism (RFLP), was localized to intron 6, and the rare allele was less common among Italian alcoholics with clinical signs of liver cirrhosis, as compared to controls. Several other mutations in the CYP2E1 gene were found to be associated with this allele. However, further research is needed to relate the CYP2E1 gene polymorphism with incidence of liver cirrhosis.
Ingelman-Sundberg
M
M
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Johansson
I
I
Yin
H
H
Terelius
Y
Y
Eliasson
E
E
Clot
P
P
Albano
E
E
D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D005609:Free Radicals; D005786:Gene Expression Regulation; D008106:Liver Cirrhosis, Experimental / Q000209:etiology; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013379:Substrate Specificity
D005609:Free Radicals; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating