Archives of Toxicology

, 82:573

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

  • Tim O. Lankisch
  • Tracey C. Gillman
  • Thomas J. Erichsen
  • Ursula Ehmer
  • Sandra Kalthoff
  • Nicole Freiberg
  • Peter A. Munzel
  • Michael P. Manns
  • Christian P. Strassburg
Molecular Toxicology

DOI: 10.1007/s00204-008-0347-1

Cite this article as:
Lankisch, T.O., Gillman, T.C., Erichsen, T.J. et al. Arch Toxicol (2008) 82: 573. doi:10.1007/s00204-008-0347-1

Abstract

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.

Keywords

UDP glucuronosyltransferase Transcriptional regulation Dioxin Single nucleotide polymorphism UGT1A3 Xenobiotic response element Aryl hydrocarbon receptor 

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Tim O. Lankisch
    • 1
  • Tracey C. Gillman
    • 1
  • Thomas J. Erichsen
    • 1
  • Ursula Ehmer
    • 1
  • Sandra Kalthoff
    • 1
  • Nicole Freiberg
    • 1
  • Peter A. Munzel
    • 2
  • Michael P. Manns
    • 1
  • Christian P. Strassburg
    • 1
  1. 1.Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
  2. 2.Department of Toxicology, Institute of Pharmacology and ToxicologyUniversity of TubingenTübingenGermany

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