TY - JOUR T1 - Novel Single Nucleotide Polymorphisms in the Promoter and Intron 1 of Human Pregnane X Receptor/NR1I2 and Their Association with CYP3A4 Expression JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 169 LP - 181 DO - 10.1124/dmd.107.016600 VL - 36 IS - 1 AU - Lamba, Jatinder AU - Lamba, Vishal AU - Strom, Stephen AU - Venkataramanan, Raman AU - Schuetz, Erin Y1 - 2008/01/01 UR - http://dmd.aspetjournals.org/content/36/1/169.abstract N2 - The hypothesis was tested that sequence diversity in pregnane X receptor (PXR) cis-regulatory regions is a significant determinant of variation in inducible and constitutive CYP3A4 expression. A combination of comparative genomics and computational algorithms was used to select regions of the human PXR promoter and intron 1 that were resequenced in the polymorphism discovery resource 24 DNA subset. PXR single nucleotide polymorphisms (SNP) were then genotyped in donor human livers phenotyped for CYP3A4 and multidrug resistance protein 1 mRNA and primary human hepatocytes phenotyped for basal and rifampin-inducible CYP3A4 activity. The human PXR promoter [16.9 kilobase (kb)] was significantly larger than in rodents (2.9 kb). Eighty-nine SNPs were identified in the promoter and intron 1 of PXR. The SNPs most consistently associated with CYP3A4 phenotypic measures were a 44477T&gt;C(-1359) promoter SNP (in linkage disequilibrium with SNP 463970, a 6-base pair deletion in intron 1a, and SNP 46551, a C nucleotide insertion in intron 1b); SNP 63396C&gt;T in intron 1 (in linkage disequilibrium with SNP 63704A&gt;G, a 63813(CAAA)(CA) variable repeat, and SNP 65104T&gt;C); and SNP 56348C&gt;A, SNP 69789A&gt;G, and SNP 66034T&gt;C. Donor livers with the variant PXR alleles had altered hepatic expression of PXR targets compared with livers with PXR wild-type alleles. These results identified PXR promoter and intron 1 SNPs associated with PXR target gene expression (CYP3A4) in donor livers and cultured hepatocytes and that a striking number of the linked intron 1 SNPs will affect putative binding sites for hepatic nuclear factor 3β (FOXA2), a transcription factor linked with PXR expression. The American Society for Pharmacology and Experimental Therapeutics ER -