Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nuclecticle polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp -219 and - 163 UGTI A4 i i i i b 40% transcr pt on was occurred in 9% among 109 blood donors reducing UGTlA4 transcr pt on y. dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGTIA4 gene expression and induction was aryl hydrocarbon receptor (AhR)dependent, and reduced in the presence ofSNPs at bp -219 and - 163. AhR-mediated regulation of the human UGTIA4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism. (c) 2008 Elsevier Inc. All rights reserved