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Abstract

Mechanisms that protect the body from a diverse array of harmful chemicals are also involved in drug metabolism, and can cause adverse drug-drug interactions. Two closely related orphan nuclear hormone receptors--the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR)--have recently emerged as transcriptional regulators of cytochrome P450 expression that couple xenobiotic exposure to oxidative metabolism. In this review, we provide an examination of the roles of PXR and CAR as xenobiotic sensors, and discuss the application of this knowledge to toxicological screening in drug discovery.

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The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

J L Staudinger, B. Goodwin, S Jones … (2001)

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

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An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.

Steven Kliewer, John T. Moore, Laura Wade … (1998)

Steroid hormones exert profound effects on differentiation, development, and homeostasis in higher eukaryotes through interactions with nuclear receptors. We describe a novel orphan nuclear receptor, termed the pregnane X receptor (PXR), that is activated by naturally occurring steroids such as pregnenolone and progesterone, and synthetic glucocorticoids and antiglucocorticoids. PXR exists as two isoforms, PXR.1 and PXR.2, that are differentially activated by steroids. Notably, PXR.1 is efficaciously activated by pregnenolone 16alpha-carbonitrile, a glucocorticoid receptor antagonist that induces the expression of the CYP3A family of steroid hydroxylases and modulates sterol and bile acid biosynthesis in vivo. Our results provide evidence for the existence of a novel steroid hormone signaling pathway with potential implications in the regulation of steroid hormone and sterol homeostasis.

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

J Lehmann, D D McKee, M Watson … (1998)

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.

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PubMed ID:: 12120277

DOI:: 10.1038/nrd753

ScienceOpen disciplines: Chemistry

Keywords: Animals,Aryl Hydrocarbon Hydroxylases,Cytochrome P-450 CYP2B6,Cytochrome P-450 CYP3A,Cytochrome P-450 Enzyme System,genetics,Gene Expression Regulation, Enzymologic,Humans,Oxidoreductases, N-Demethylating,Receptors, Cytoplasmic and Nuclear,chemistry,physiology,Receptors, Steroid,Transcription Factors,Xenobiotics,metabolism

PXR, CAR and drug metabolism.

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Abstract

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Drug_transporters

Most cited references 73

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.

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

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