Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene.
UDP-glucuronosyltransferases contribute to the detoxification of drugs by forming water soluble beta-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.
Lankisch
Tim O
TO
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Strasse 1, Hannover, Germany.
Gillman
Tracey C
TC
Erichsen
Thomas J
TJ
Ehmer
Ursula
U
Kalthoff
Sandra
S
Freiberg
Nicole
N
Munzel
Peter A
PA
Manns
Michael P
MP
Strassburg
Christian P
CP
D020121:5' Untranslated Regions / Q000235:genetics; D000483:Alleles; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D017931:DNA Primers; D004967:Estrogens / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000201:enzymology; D008156:Luciferases / Q000235:genetics; D016296:Mutagenesis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000494:pharmacology
D020121:5' Untranslated Regions; D001647:Bile Acids and Salts; D017931:DNA Primers; D004967:Estrogens; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; D008156:Luciferases; C122075:UDP-glucuronosyltransferase, UGT1A3; D014453:Glucuronosyltransferase