Abstract
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 γ-interferon activated sequence. Inflammation and interferon (IFN)-γ 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-γ and to examine the influence of the nucleotide substitutions on this function. Treatment of HepG2 cells with IFN-γ, 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-γ suppresses native CYP2E1 promoter activity and that the -71G is critical for this response.
Footnotes
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This work was supported in part by National Institute of Environmental Health Sciences, R01 ES08953-01, and an intramural grant from the University of Louisville School of Medicine.
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DOI: 10.1124/jpet.103.057208.
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ABBREVIATIONS: GAS, γ-interferon activation sequence; IFN-γ, interferon-γ; HNF, hepatocyte nuclear factor.
- Received July 16, 2003.
- Accepted October 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Suppression of Cytochrome P450 2E1 Promoter Activity by Interferon-γ and Loss of Response Due to the -71G>T Nucleotide Polymorphism of the CYP2E1*7B Allele
