Genetic Polymorphisms in the TATA box and Upstream Phenobarbital-Responsive Enhancer Module of the UGT1A1 Promoter Have Combined Effects on UGT1A1 Transcription Mediated by CAR, PXR, or GR in Human Liver. Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] Journal article | | Title | Genetic Polymorphisms in the TATA box and Upstream Phenobarbital-Responsive Enhancer Module of the UGT1A1 Promoter Have Combined Effects on UGT1A1 Transcription Mediated by CAR, PXR, or GR in Human Liver. | | Author(s) | Li Y, Buckley D, Wang S, Klaassen CD, Zhong XB | | Institution | University of Kansas Medical Center. | | Source | Drug Metab Dispos 2009 Jun 18. | | Abstract | Transcription of UGT1A1 is regulated by the transcription factors CAR, PXR, GR, HNF1alpha, and HNF4alpha. 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. Polymorphism of A(TA)5-8TAA in the UGT1A1 TATA box and a SNP of -3279T>G in PBREM were genotyped in 98 human liver samples. Relative mRNA levels of CAR, PXR, GR, HNF1alpha, HNF4alpha, 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 HNF1alpha or HNF4alpha, were abolished in the samples with the combined genotype of TA7/7 plus -3279 G/G, which were also associated with significantly lower UGT1A1 mRNA levels compared to 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 to 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 HNF1alpha or HNF4alpha. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19541828 |
|
|
| |
Advertise on this site.
| | |
|
