Received for publication March 9, 2009.
Revised June 15, 2009.
Accepted for publication June 16, 2009.

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

Abstract

Transcription of UGT1A1 is regulated by the transcription factors CAR, PXR, GR, HNF1, 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. 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, 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, 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 HNF1 or HNF4.

Key words: CAR, genetic polymorphism, genotype, PXR, UDP glucuronyltransferases