Abstract
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) 1α, and HNF4α. 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)5–8TAA 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, HNF1α, HNF4α, 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 HNF1α or HNF4α, 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)7TAA and –3279G decrease UGT1A transcription mediated by CAR, PXR, or GR but not by HNF1α or HNF4α.
Footnotes
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This work was supported by the National Institutes of Health National Center for Research Resources [COBRE 5P20-RR021940].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027409.
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ABBREVIATIONS: Pol II, polymerase II; TSS, transcriptional start site; DPE, downstream promoter element; UGT1A1, UDP-glucuronosyltransferase 1A1; PBREM, phenobarbital-responsive enhancer module; CAR, constitutive androstane receptor; PXR, pregnane X receptor; GR, glucocorticoid receptor; SNP, single nucleotide polymorphism; HNF, hepatocyte nuclear factor; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; PCR, polymerase chain reaction; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LD, linkage disequilibrium.
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↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Accepted June 16, 2009.
- Received March 4, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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