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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >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.
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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.

机译：UGT1A1启动子的TATA框和上游苯巴比妥响应增强子模块中的遗传多态性对人肝脏中组成型雄烷受体，孕烷X受体或糖皮质激素受体介导的UDP-葡萄糖醛糖基转移酶1A1转录具有联合作用。

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摘要

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.
机译：UDP-葡萄糖醛酸糖基转移酶（UGT）1A1的转录受转录因子，组成型雄甾烷受体（CAR），孕烷X受体（PXR），糖皮质激素受体（GR），肝细胞核因子（HNF）1α和HNF4α调节。这项研究的目的是确定是否在RNA聚合酶II核心启动子和UGT1A1启动子的上游苯巴比妥反应元件模块（PBREM）的遗传多态性对转录因子介导的UGT1A1转录有联合作用。在98个人类肝脏样品中对UGT1A1 TATA盒中A（TA）（5-8）TAA的多态性和PBREM中-3279T> G的单核苷酸多态性进行了基因分型。 CAR，PXR，GR，HNF1 alpha，HNF4 alpha和UGT1A1的相对mRNA水平通过多重分支DNA技术进行定量。建立了具有不同组合遗传多态性的肝样品中UGT1A1与转录因子之间的mRNA水平相关性。具有联合基因型TA7 / 7加-3279G / G的样品中，取消了UGT1A1与CAR，PXR或GR之间的mRNA水平的相关性，但没有取消HNF1 alpha或HNF4 alpha的相关性，这也与UGT1A1 mRNA的显着降低有关水平与其他组合基因型相比。在联合基因型TA6 / 7加-3279 G / G的样品中，UGT1A1与CAR或PXR之间的mRNA水平相关性降低了，但没有消除，与联合基因型TA6 / 7 plus相比，UGT1A1 mRNA水平明显降低-3279T / G和其他含有TA6 / 6的基因型。总之，包含A（TA）（7）TAA和-3279G的组合基因型减少了CAR，PXR或GR介导的UGT1A转录，但没有HNF1 alpha或HNF4 alpha介导。

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