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Research ArticleArticle

Novel Single Nucleotide Polymorphisms in the Promoter and Intron 1 of Human Pregnane X Receptor/NR1I2 and Their Association with CYP3A4 Expression

Jatinder Lamba, Vishal Lamba, Stephen Strom, Raman Venkataramanan and Erin Schuetz
Drug Metabolism and Disposition January 2008, 36 (1) 169-181; DOI: https://doi.org/10.1124/dmd.107.016600
Jatinder Lamba
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Vishal Lamba
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Stephen Strom
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Raman Venkataramanan
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Erin Schuetz
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Abstract

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>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>T in intron 1 (in linkage disequilibrium with SNP 63704A>G, a 63813(CAAA)(CA) variable repeat, and SNP 65104T>C); and SNP 56348C>A, SNP 69789A>G, and SNP 66034T>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.

Footnotes

  • J.L. and V.L. contributed equally to this work.

  • This work is supported in part by the National Institutes of Health (NIH) Grant GM60346, NIH/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org) under Grant U01 GM61393, and the NIH P30 CA21765 Cancer Center Support Grant, and by the American Lebanese Syrian Associated Charities (ALSAC).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.016600.

  • ABBREVIATIONS: NR1I2/PXR, pregnane X receptor; PAR2, proteinase-activated receptor-2; MDR1, multidrug resistance protein 1; SNP, single nucleotide polymorphism; kb, kilobase; TF, transcription factor(s); HNF, hepatic nuclear factor; CEBP, CCAAT enhancer binding protein; NF, nuclear factor; ECR, evolutionary conserved region; PCR, polymerase chain reaction; bp, base pair; AAT1, testis-specific AMY-1 binding protein; GSK3B, glycogen synthase kinase-3β; STAT, signal transducer and activator of transcription; LD, linkage disequilibrium; IBD, inflammatory bowel disease.

    • Received May 11, 2007.
    • Accepted October 5, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (1)
Drug Metabolism and Disposition
Vol. 36, Issue 1
1 Jan 2008
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Research ArticleArticle

Novel Single Nucleotide Polymorphisms in the Promoter and Intron 1 of Human Pregnane X Receptor/NR1I2 and Their Association with CYP3A4 Expression

Jatinder Lamba, Vishal Lamba, Stephen Strom, Raman Venkataramanan and Erin Schuetz
Drug Metabolism and Disposition January 1, 2008, 36 (1) 169-181; DOI: https://doi.org/10.1124/dmd.107.016600

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Research ArticleArticle

Novel Single Nucleotide Polymorphisms in the Promoter and Intron 1 of Human Pregnane X Receptor/NR1I2 and Their Association with CYP3A4 Expression

Jatinder Lamba, Vishal Lamba, Stephen Strom, Raman Venkataramanan and Erin Schuetz
Drug Metabolism and Disposition January 1, 2008, 36 (1) 169-181; DOI: https://doi.org/10.1124/dmd.107.016600
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