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

Citation
J. Zhang et al., The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants, PHARMACOGEN, 11(7), 2001, pp. 555-572
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACOGENETICS
ISSN journal
0960-314X → ACNP
Volume
11
Issue
7
Year of publication
2001
Pages
555 - 572
Database
ISI
SICI code
0960-314X(200110)11:7<555:THPXRG>2.0.ZU;2-Q
Abstract
The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcr iptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by e ndobiotics and xenobiotics. We cloned the human PXR gene and analysed the s equence in DNAs of individuals whose CYP3A phenotype was known. The PXR gen e spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thir ty-eight single nucleotide polymorphisms (SNPs) were identified including s ix SNPs in the coding region. Three of the coding SNPs are non-synonymous c reating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); a nd PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African A mericans and was never found in Caucasians. Hepatic expression of CYP3A4 pr otein 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 R122 Q, (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 lig and activation of the CYP3A4 reporter plasmids in transient transfection as says. However, the person heterozygous for PXR*4 is normal for CYP3A4 metab olism 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 stati stical analysis. Because ligand activation of PXR and upregulation of a sys tem of drug detoxification genes are major determinants of drug interaction s, it will now be useful to extend this work to determine the association o f these common PXR SNPs to human variation in induction of other drug detox ification gene targets. Pharmacogenctics 11:555-572 (C) 2001 Lippincott Wil liams & Wilkins.