The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

Abstract

The cytochrome P-450 monooxygenase 3A4 (CYP3A4) is responsible for the oxidative metabolism of a wide variety of xenobiotics including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, has remained unclear. We report the identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. Comparison of hPXR with the recently cloned mouse PXR reveals marked differences in their activation by certain drugs, which may account in part for the species-specific effects of compounds on CYP3A gene expression. These findings provide a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provide a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

“…It has been well characterized that CYP3A4 gene is regulated by PXR [5][6][7][8], CAR [4], and VDR [9,10]. Induction of Cyp3a11 (homologous of human CYP3A4) mRNA by retinoids in hepatocytes which are deficient in both PXR and CAR would strongly suggest the role of VDR in regulation of Cyp3a11.…”

“…It also participates in the metabolism of xenobiotics and bio-activation of environmental pro-carcinogens. Several members of the nuclear receptor superfamily including CAR [4], PXR [5][6][7][8], VDR [9,10], and the glucocorticoid receptor (GR) [11] have been shown to be responsible for endobiotic-and xenobiotic-mediated CYP3A induction. Human PXR (hPXR) or steroids and xenobiotic receptor (SXR) [12,13], CAR [4], and VDR [9,10] control CYP3A4 expression by targeting the same cis-acting elements located in the regulatory region of target genes.…”

Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor

“…CYP3A4 expression is transcriptionally regulated by members of the NR1I nuclear receptor subfamily of ligandactivated transcription factors, which constitutes the human pregnane X receptor (hPXR; NR1I2) [3,5,6], the vitamin D 3 receptor (VDR; NR1I1) [7] and the constitutive androstane receptor (CAR; NRI3) [8,9]. Only a few agonists are known for CAR and VDR, while PXR is activated by a wide variety of structurally unrelated compounds that include rifampicin, phenobarbital and hyperforin, but also anticancer drugs like paclitaxel [10] and tamoxifen [11].…”

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

“…Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9].…”