Polymorphism of the human alcohol dehydrogenase 4 (ADH4) promoter affects gene expression

Pharmacogenetics. 1999 Feb;9(1):25-30. doi: 10.1097/00008571-199902000-00004.


The human alcohol dehydrogenase 4 gene (ADH4) encodes the human pi-alcohol dehydrogenase (pi-ADH), which can contribute to ethanol metabolism at moderate and high concentrations of ethanol. There are no known structural variants of pi-ADH in humans. We report the first polymorphisms in the ADH4 gene, at three sites in the promoter: -192 bp, -159 bp and -75 bp, respectively. To determine whether these variations affected promoter function, different haplotypes of the ADH4 proximal promoter were subcloned into a luciferase reporter vector, and the relative promoter activity analysed in hepatoma cells. One of the three sites had a dramatic effect on promoter activity, while the others did not detectably affect activity. The -75A allele had promoter activity more than twice that of the -75C allele. Alcohol dehydrogenase activity is rate limiting for ethanol oxidation. We hypothesize that the different ADH4 alleles lead to different amounts of pi-ADH in liver, which affects the risk for alcoholism by modulating alcohol metabolism.

Publication types

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

MeSH terms

  • Alcohol Dehydrogenase / genetics*
  • Base Sequence
  • Cloning, Molecular
  • DNA Primers
  • Gene Expression / genetics*
  • Humans
  • Isoenzymes / genetics*
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Tumor Cells, Cultured


  • DNA Primers
  • Isoenzymes
  • Alcohol Dehydrogenase