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Hum Mol Genet. 2014 Oct 15;23(20):5558-69. doi: 10.1093/hmg/ddu268. Epub 2014 May 30.

Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver.

Author information

1
Department of Medicine and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA and.
2
Department of Medicine and.
3
Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
4
Department of Medicine and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
5
Department of Psychiatry, The University of Illinois at Chicago, Chicago, IL 60612, USA.
6
Department of Medicine and mratain@medicine.bsd.uchicago.edu.

Abstract

The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74-217% and 52%, 39-105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 6-58%; 47%, 9-58%; and 52%, 24-75%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs.

PMID:
24879639
PMCID:
PMC4168829
DOI:
10.1093/hmg/ddu268
[Indexed for MEDLINE]
Free PMC Article

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