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

J Pharmacol Exp Ther. 2004 Jan;308(1):284-8. doi: 10.1124/jpet.103.057208. Epub 2003 Oct 17.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Cytochrome P-450 CYP2E1 / genetics*
  • Cytochrome P-450 CYP2E1 / metabolism
  • Gene Expression Regulation / drug effects*
  • Humans
  • Interferon-gamma / pharmacology*
  • Polymorphism, Genetic
  • Promoter Regions, Genetic / drug effects*
  • Tumor Cells, Cultured

Substances

  • Interferon-gamma
  • Cytochrome P-450 CYP2E1