Genetic polymorphisms in the TATA box and upstream phenobarbital-responsive enhancer module of the UGT1A1 promoter have combined effects on UDP-glucuronosyltransferase 1A1 transcription mediated by constitutive androstane receptor, pregnane X receptor, or glucocorticoid receptor in human liver.
Transcription of UDP-glucuronosyltransferase (UGT) 1A1 is regulated by the transcription factors, constitutive androstane receptor (CAR), pregnane X receptor (PXR), glucocorticoid receptor (GR), hepatocyte nuclear factor (HNF) 1 alpha, and HNF4 alpha. The purpose of this study was to determine whether the genetic polymorphisms in the RNA polymerase II core promoter and the upstream phenobarbital-responsive element module (PBREM) of the UGT1A1 promoter have combined effects on UGT1A1 transcription mediated by the transcription factors. A polymorphism of A(TA)(5-8)TAA in the UGT1A1 TATA box and a single nucleotide polymorphism of -3279T>G in PBREM were genotyped in 98 human liver samples. Relative mRNA levels of CAR, PXR, GR, HNF1 alpha, HNF4 alpha, and UGT1A1 were quantified by a multiplex branched DNA technique. Correlations of mRNA levels between UGT1A1 and the transcription factors were established in liver samples with different combined genetic polymorphisms. Correlation of mRNA levels between UGT1A1 and CAR, PXR, or GR, but not HNF1 alpha or HNF4 alpha, was abolished in the samples with the combined genotype of TA7/7 plus -3279G/G, which was also associated with significantly lower UGT1A1 mRNA levels compared with other combined genotypes. Correlations of mRNA levels between UGT1A1 and CAR or PXR were reduced but not abolished in the samples with the combined genotype of TA6/7 plus -3279 G/G, which showed significantly lower UGT1A1 mRNA levels compared with the combined genotype of TA6/7 plus -3279T/G and other genotypes containing TA6/6. In conclusion, the combined genotypes containing A(TA)(7)TAA and -3279G decrease UGT1A transcription mediated by CAR, PXR, or GR but not by HNF1 alpha or HNF4 alpha.
Li
Ye
Y
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Buckley
David
D
Wang
Shuang
S
Klaassen
Curtis D
CD
Zhong
Xiao-bo
XB
D000090702:Constitutive Androstane Receptor; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D016385:TATA Box / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D000099148:UGT1A1 Enzyme
D000090702:Constitutive Androstane Receptor; D014453:Glucuronosyltransferase; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D047493:PPAR alpha; D010634:Phenobarbital; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D000099148:UGT1A1 Enzyme; C496487:HNF1A protein, human; C496592:HNF4A protein, human