Suppression of cytochrome P450 2E1 promoter activity by interferon-gamma and loss of response due to the -71G>T nucleotide polymorphism of the CYP2E1*7B allele.
The CYP2E1*7B allele is defined by two nucleotide sequence polymorphisms, -71G>T and -333T>A. The CYP2E1 promoter sequence flanking the -71G nucleotide is consistent with a gamma-interferon activated sequence. Inflammation and interferon (IFN)-gamma suppress expression of CYP2E1 in vivo; however, the exact mechanism is not known. The objectives of this study were to determine whether the CYP2E1 promoter is regulated by IFN-gamma and to examine the influence of the nucleotide substitutions on this function. Treatment of HepG2 cells with IFN-gamma, after transient transfection with a luciferase reporter gene bearing the native CYP2E1 (-71G) promoter sequence resulted, in a dose-dependent reduction of luciferase activity. In contrast, no suppression was observed in cells transfected with the *7B allele promoter (-333A and -71T) nor a CYP2E1 plasmid containing only the -71T polymorphism. These data indicate that IFN-gamma suppresses native CYP2E1 promoter activity and that the -71G is critical for this response.
Qiu
Ling O
LO
Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Linder
Mark W
MW
Antonino-Green
Deborah M
DM
Valdes
Roland
R
D000483:Alleles; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D007371:Interferon-gamma; D019392:Cytochrome P-450 CYP2E1