The -75A allele of the ADH4 promoter demonstrated more than twice the promoter activity of the -75C allele in hepatoma cells, potentially modulating alcohol metabolism.
Does polymorphism in the ADH4 promoter affect gene expression in hepatoma cells?
Polymorphisms in the ADH4 promoter, specifically the -75A allele, significantly increase promoter activity compared to the -75C allele, potentially affecting alcohol metabolism and alcoholism risk.
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.
Edenberg et al. (Mon,) reported a other. -75A allele of the ADH4 promoter vs. -75C allele was evaluated on Relative promoter activity in hepatoma cells. The -75A allele of the ADH4 promoter demonstrated more than twice the promoter activity of the -75C allele in hepatoma cells, potentially modulating alcohol metabolism.