Abstract

The discovery of the Pregnane X receptor (PXR) has led to a greater understanding of the fundamental mechanisms underlying upregulation of cytochrome P4503A and potentially other drug detoxification enzymes. We hypothesize that sequence variations (including single nucleotide polymorphisms, SNPs) in PXR or its cognate binding element (PXRE) in the CYP3A4 gene are central to human variation in both basal and inducible CYP3A expression. To critically study the importance of PXR SNPs to regulation of CYP3A a safe, reliable, and convenient assay will be needed to determine an individual s PXR genotype. Towards this goal we have cloned, mapped and are sequencing PXR. Our overall objectives are: (1) to identify sequence variations in PXR (or in the CYP3A4 PXRE) and determine their functional importance; (2) to correlate PXR SNPs to phenotypic variations in CYP3A; (3) to determine the overall frequency and pattern of sequence variations in PXR; and (4) to determine the functional importance of PXR SNPs and the molecular mechanisms leading to non- functional PXR in cellular and biochemical assays. Our pharmacogenomic approach takes advantage of our unique resources - genomic DNAs from CYP3A phenotyped human tissues and human study populations from numerous clinical trials with CYP3A substrates and inducers. Additionally, using cultures of human hepatocytes phenotyped for CYP3A induction we will prospectively identify the outliers in inductive drug response. The goal of our study is to use these defined patient populations simultaneously as a source of genotype-phenotype relationships and as a SNP discovery resource. Our hypothesis driven approach will immediately elucidate the functional consequences of PXR or PXRE SNPs to not only PXR function but CYP3A drug response as well and will serve as an important gentotype-phenotype/SNP pharmacogenomics model and provide further insights into mechanisms responsible for the highly variable pharmacokinetics of CYP3A metabolized drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060346-04
Application #
6636367
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Long, Rochelle M
Project Start
2000-03-01
Project End
2004-02-29
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
4
Fiscal Year
2003
Total Cost
$244,244
Indirect Cost

  Institution

Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105

  Publications

Yasuda, Kazuto; Cline, Cynthia; Lin, Yvonne S et al. (2015) In Vivo Imaging of Human MDR1 Transcription in the Brain and Spine of MDR1-Luciferase Reporter Mice. Drug Metab Dispos 43:1646-54
Brown, Kevin C; Hosseinipour, Mina C; Hoskins, Janelle M et al. (2012) Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians. Pharmacogenomics 13:113-21
Nagai, Shinjiro; Takenaka, Kazumasa; Nachagari, Deepa et al. (2011) Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. Cancer Res 71:1781-91
Yang, Xia; Zhang, Bin; Molony, Cliona et al. (2010) Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 20:1020-36
Lamba, Vishal; Panetta, John C; Strom, Stephen et al. (2010) Genetic predictors of interindividual variability in hepatic CYP3A4 expression. J Pharmacol Exp Ther 332:1088-99
Chaudhry, Amarjit S; Urban, Thomas J; Lamba, Jatinder K et al. (2010) CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther 332:599-611
Lin, Yvonne S; Yasuda, Kazuto; Assem, Mahfoud et al. (2009) The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation. Drug Metab Dispos 37:1295-304
Perera, M A; Thirumaran, R K; Cox, N J et al. (2009) Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans. Pharmacogenomics J 9:49-60
Lamba, Jatinder; Lamba, Vishal; Strom, Stephen et al. (2008) Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos 36:169-81
Yasuda, Kazuto; Ranade, Aarati; Venkataramanan, Raman et al. (2008) A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos 36:1689-97

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