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

Abstract

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) 1␣, and HNF4␣. 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␣, HNF4␣, 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␣ or HNF4␣, 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␣ or HNF4␣.

Prolonged Hyperbilirubinemia in a Neonate with a Novel Mutation in the <b><i>UDP-glucuronosyltransferase 1A1</i></b> Gene

“…The allele frequency of c.-3279T>G is as high as 0.39 in the general Caucasian population [12], which is similar to that in the Taiwanese population (0.37) [5]. However, such a mutation is often ignored when the UGT1A1 gene is analyzed [5].…”

“…Sugatani et al [8 ]and Li et al [12 ]reported that the c.-3279T>G polymorphism is associated with a decrease in UGT transcription and that individuals carrying that polymorphic mutation are at a high risk of developing Gilbert's syndrome and irinotecan toxicity. The allele frequency of c.-3279T>G is as high as 0.39 in the general Caucasian population [12], which is similar to that in the Taiwanese population (0.37) [5].…”

Crigler-Najjar syndrome in The Netherlands: Identification of four novelUGT1A1alleles, genotype–phenotype correlation, and functional analysis of 10 missense mutants

“…Residual UGT1A1 activity in this patient may therefore be derived from the other allele that appears to have a normal coding region but may contain the UGT1A1Ã28 promoter polymorphism. This allele might also contain additional polymorphisms such as the g.À3279T4G of which was reported recently that, in combination with the UGT1A1Ã28 polymorphism, results in further reduction of UGT1A1 expression [Li et al, 2009].…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…Interestingly, in the gtPBREM cluster a polymorphism (T3279G) was found in linkage disequilibrium with the UGT1A1*28 polymorphism which synergistically lowers UGT1A1 expression [84,85].…”