title: Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver.
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.
authors.affiliation: Department of Medicine and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA and.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.affiliation: Department of Medicine and.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Department of Medicine and.
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.affiliation: Department of Medicine and.
authors.forename: Peixian
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Medicine and.
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.affiliation: Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Medicine and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Department of Psychiatry, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cook
authors.affiliation: Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Medicine and mratain@medicine.bsd.uchicago.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D056915:DNA Copy Number Variations; D005786:Gene Expression Regulation; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000074435:Peroxisome-Targeting Signal 1 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014453:Glucuronosyltransferase