Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene

• Published in: Archives of toxicology 2008-09, Vol.82 (9), p.573-582
• Main Authors: Lankisch, Tim O., Gillman, Tracey C., Erichsen, Thomas J., Ehmer, Ursula, Kalthoff, Sandra, Freiberg, Nicole, Munzel, Peter A., Manns, Michael P., Strassburg, Christian P.
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; Alleles; Bile Acids and Salts - biosynthesis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Catalysis; Chemical and industrial products toxicology. Toxic occupational diseases; DNA Primers; Drug therapy; Environmental Health; Estrogens - biosynthesis; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Enzymologic - physiology; Genes, Reporter - genetics; Genotype; Glucuronosyltransferase - biosynthesis; Glucuronosyltransferase - genetics; Hepatocyte Nuclear Factor 1-alpha - biosynthesis; Humans; Liver - enzymology; Luciferases - genetics; Medical sciences; Molecular Toxicology; Mutagenesis; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Proteins; Receptors, Aryl Hydrocarbon - physiology; Reverse Transcriptase Polymerase Chain Reaction; Toxicology; Various organic compounds; Xenobiotics - pharmacology
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-008-0347-1

UDP-glucuronosyltransferases contribute to the detoxification of drugs by forming water soluble β- d -glucopyranosiduronic acids. The human UGT1A3 protein catalyzes the glucuronidation of estrogens, bile acids and xenobiotics including non-steroidal anti-inflammatory drugs and lipid lowering drugs. Regulation of UGT1A3 by xenobiotic response elements is likely, but the responsible elements are yet uncharacterized. In addition, genetic promoter variants may affect UGT1A3 regulation and potential induction by xenobiotics. The UGT1A3 promoter was analyzed by mutagenesis, reporter gene, and mobility shift analyses. Three hundred and eighty-nine blood donors were genotyped for promoter single nucleotide polymorphisms (SNPs) showing an allelic frequency of 42% of variants at −66 (T to C) and −204 (A to G). A xenobiotic response element regulating aryl hydrocarbon receptor (AhR)-mediated UGT1A3 transcription was identified and characterized. UGT1A3 transcription was reduced in the presence of promoter SNPs. These data demonstrate xenobiotic induced regulation of the UGT1A3 gene by the AhR, which shows genetic variability.