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Shared regulation of UGT1A7 by hepatocyte nuclear factor (HNF) 1alpha and HNF4alpha

Ursula Ehmer1, Sandra Kalthoff, Tim O Lankisch

  • 1Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|April 22, 2010
PubMed

Insights

Hepatocyte nuclear factors (HNFs) activate the UDP-glucuronosyltransferase (UGT) 1A7 gene, influencing its tissue-specific expression. Single nucleotide polymorphisms (SNPs) in UGT1A7 can affect this activation.

Area of Science:

  • Pharmacogenomics
  • Molecular biology
  • Biochemistry

Background:

  • Glucuronidation metabolizes drugs and carcinogens via UDP-glucuronosyltransferases (UGTs).
  • The UGT1A7 gene, crucial for metabolizing xenobiotics, is expressed in the GI tract and lung, but not the liver.
  • Transcriptional regulation of UGT1A7 and the impact of single nucleotide polymorphisms (SNPs) remain poorly understood.

Purpose of the Study:

  • To investigate the transcriptional regulation of the UGT1A7 gene.
  • To identify the role of hepatocyte nuclear factors (HNFs) in UGT1A7 gene expression.
  • To elucidate how SNPs influence UGT1A7 regulation and tissue-specific expression.

Main Methods:

  • Sequence analysis and mutagenesis of the UGT1A7 promoter.
  • Reporter gene assays and small interfering RNA (siRNA) silencing.
  • Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSAs).

Main Results:

  • Five HNF binding sites in the UGT1A7 promoter were identified, regulated by HNF1alpha and HNF4alpha.
  • HNF1alpha activation was reduced by the UGT1A7 -57G SNP.
  • HNF4alpha activation of UGT1A7 was weaker and required higher concentrations compared to UGT1A9, correlating with tissue expression differences.

Conclusions:

  • Hepatocyte nuclear factors (HNFs) play a specific role in the transcriptional control of UGT1A7.
  • The identified HNF binding sites and SNP effects contribute to UGT1A7's tissue-specific expression and function.
  • Understanding UGT1A7 regulation is vital for predicting drug metabolism and toxicity across different tissues.

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