The human nuclear pregnane X receptor (PXR) activates cytochrome P450-3A (124010) expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions.

Lehmann et al. (1998) identified a nuclear receptor, termed PXR, that binds to the rifampicin/dexamethasone response element in the CYP3A4 (124010) promoter as a heterodimer with the 9-cis retinoic acid receptor RXR (see 180245). The human PXR is related to the mouse Pxr1, which they had cloned and shown to be activated by dexamethasone, pregnenolone 16-alpha-carbonitrile (PCN), and other compounds known to induce expression of the CYP3A1 gene, the predominant form of CYP3A in rat liver and intestine. Lehmann et al. (1998) isolated PXR clones from a human liver cDNA library. Amino acid sequence comparison showed that human PXR shared 96% and 76% sequence identity with mouse Pxr1 in the DNA-binding and ligand-binding domains, respectively. Initiation of translation at a CUG initiation codon would yield a protein of 434 amino acids. Northern blot analysis detected most abundant expression in liver, colon, and small intestine; transcripts of 2.6, 4.3, and 5 kb were present in each of these tissues. Lehmann et al. (1998) provided several lines of evidence indicating that human PXR serves as a key transcriptional regulator of the CYP3A4 gene.

By homology searching an EST database for orphan nuclear receptors, Bertilsson et al. (1998) identified NR1I2, which they called PAR. They isolated 2 PAR cDNAs, which they termed PAR1 and PAR2, that differ only in their 5-prime end. The authors suggested that the PAR1 and PAR2 cDNAs represent alternatively spliced PAR transcripts. The predicted initiation codon of PAR1 is CUG, whereas that of PAR2 is AUG. The deduced PAR1 and PAR2 proteins contain DNA- and ligand-binding domains. PAR is related to mouse Pxr, human VDR (601769), and human MB67 (603881).

Crystal Structure

Watkins et al. (2001) determined the crystal structure of the ligand-binding domain of PXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of PXR contains a small number of polar residues, permitting SR12813 to bind in 3 distinct orientations. The position and nature of these polar residues are critical for establishing the precise pharmacologic activation profile of PXR.

Zhang et al. (2001) determined that the PXR gene contains 9 exons and spans 35 kb of genomic DNA.

Zhang et al. (2001) mapped the human PXR gene to chromosome 3q13-q21 by analysis of radiation hybrids and by fluorescence in situ hybridization.

Bertilsson et al. (1998) found that PAR is efficiently activated by pregnanes and by clinically used drugs known to selectively induce the expression of human CYP3A. PAR was not activated by pregnenolone 16-alpha-carbonitrile, which is a potent inducer of mouse Cyp3a genes and an activator of the mouse receptor Pxr.1. The authors showed that PAR binds to and transactivates through a conserved regulatory sequence present in human but not mouse CYP3A genes. Bertilsson et al. (1998) suggested that PAR mediates a signaling pathway that is important for the regulation of CYP3A gene expression. Northern blot analysis of human adult tissues detected a major 3.4- and minor 4.9- and 6.6-kb PAR transcripts in liver, colon, and small intestine; PAR expression was not found in any other examined tissue. In situ hybridization of human embryo showed that PAR expression was limited to cells of the intestinal mucosal layer.

CYP3A4 (124010) is responsible for the oxidative metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. The findings of Lehmann et al. (1998) provided a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provided a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.

An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biologic activity. Much of the detoxification is performed by cytochrome P450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes; therefore, they would appear to be integrated into a coordinated metabolic pathway. Instead of possessing hundreds of receptors, 1 for each inducing compound, Blumberg et al. (1998) proposed the existence of a few broad-specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, Blumberg et al. (1998) identified NR1I2, which they termed SXR, a nuclear receptor that activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes (e.g., CYP3A4; 124010) and is expressed in tissues in which these catabolic enzymes are expressed. Blumberg et al. (1998) suggested that broad-specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.

Synold et al. (2001) showed that SXR regulates drug efflux by activating expression of the MDR1 gene (171050). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein-mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. Synold et al. (2001) also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. Their findings demonstrated how the molecular activities of SXR can be manipulated to control drug clearance.

Masuyama et al. (2003) examined the expression and potential role of the PXR-CYP3A pathway in endometrial cancer tissues. Tissues showing high PXR expression showed significantly high expression of PXR targets CYP3A4 and CYP3A7 (605340) and low expression of the estrogen receptor (ER; see 133430) compared with levels in tissues showing low PXR expression. Among endometrial cancer cell lines, HEC-1 cells, which express high PXR and low ER and progesterone receptor (607311), showed a stronger transcriptional response of the PXR-CYP3A pathway to PXR ligands than did Ishikawa cells, which express low PXR but high ER. The authors concluded that steroid/xenobiotics metabolism in tumor tissue through the PXR-CYP3A pathway might play an important role as an alternative pathway for gonadal hormone and endocrine-disrupting chemical effects on endometrial cancer expressing low ER-alpha.

By database searching, Uno et al. (2003) identified a 6-bp deletion at the putative HNF1 (142410)-binding element of PAR2, a splicing species of PXR that has an extended N terminus. Uno et al. (2003) investigated a possible association between this deletion variant and aspirin-induced asthma (AIA), a typical drug-induced phenotype due to aspirin or nonsteroidal antiinflammatory drugs. These drugs are metabolized by CYP2C9 (601130) and UGT1A6 (606431), which are regulated by PXR. No association was found.

The induction of CYP3A enzymes is species-specific and believed to involve 1 or more cellular factors, or receptor-like xenosensors. Xie et al. (2000) identified one such factor as the nuclear receptor Pxr and its human homolog SXR. Xie et al. (2000) showed that targeted disruption of the mouse Pxr gene abolished induction of CYP3A by prototypic inducers such as dexamethasone or pregnenolone-16-alpha-carbonitrile. In Pxr-null mice carrying a transgene for an activated form of human SXR, there was constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic compounds. Xie et al. (2000) demonstrated that species origin of the receptor, rather than the promoter structure of the CYP3A genes, dictates the species-specific pattern of CYP3A inducibility. Thus, they could generate 'humanized' transgenic mice that were responsive to human-specific inducers such as the antibiotic rifampicin. Xie et al. (2000) concluded that the SXR/Pxr genes encode the primary species-specific xenosensors that mediate the adaptive hepatic response, and may represent the critical biochemical mechanism of human xenoprotection.