Toggle Main Menu Toggle Search

Open Access padlockePrints

The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants

Lookup NU author(s): Professor Ann Daly

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets. Pharmacogenctics 11:555-572 (C) 2001 Lippincott Williams & Wilkins.


Publication metadata

Author(s): Daly A; Zhang J; Kuehl P; Green ED; Touchman JW; Watkins PB; Hall SD; Maurel P; Relling M; Brimer C; Yasuda K; Wrighton SA; Hancock M; Kim RB; Strom S; Thummel K; Russell CG; Hudson JR; Schuetz EG; Boguski MS

Publication type: Article

Publication status: Published

Journal: Pharmacogenetics

Year: 2001

Volume: 11

Issue: 7

Pages: 555-572

ISSN (print): 0960-314X

ISSN (electronic): 1744-6880

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1097/00008571-200110000-00003

DOI: 10.1097/00008571-200110000-00003


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share