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Pxr, car and drug metabolism

Key Points

  • Members of the cytochrome P450 (CYP) family often catalyse the first step in the detoxification of foreign substances — xenobiotics — that are ingested in our diet, breathed through the air or absorbed through our skin. CYP3A alone is responsible for the metabolism of 50–60% of all prescription drugs.

  • The expression of the genes that code for many of the CYPs that are involved in xenobiotic metabolism can be induced by xenobiotics. Although this represents an adaptive response to protect against chemical exposure, it is also the basis for an important class of drug–drug interactions, as drugs that induce CYP gene expression accelerate the metabolism of many other medications.

  • The pregnane X receptor (PXR) is a ligand-dependent transcription factor that is activated by a wide range of chemicals, including glucocorticoids, antiglucocorticoids, macrocyclic antibiotics, antifungals and herbal extracts, which have no obvious structural features in common. PXR is now widely accepted as the principal transcriptional regulator of CYP3A induction by xenobiotics.

  • The constitutive androstane receptor (CAR) regulates the expression of CYP2B, which has a more minor role in drug metabolism than CYP3A. Data indicate that there is crosstalk between CAR and PXR in the regulation of P450 enzyme expression, although the pharmacological effect of this crosstalk on drug metabolism remains to be determined.

  • The structure of PXR shows several important differences compared with other nuclear receptors, including CAR. In particular, the large, spherical ligand-binding pocket does not require ligands to satisfy a single shape or arrangement of hydrogen-bonding interactions, allowing PXR to recognize a wide range of xenobiotics.

  • Several drug interactions, such as those that involve the psychoactive component of St John's wort, hyperforin, could be attributed to inadvertent activation of PXR. To reduce the possibility of adverse interactions for future drugs, there are several levels at which PXR screening could be used:

  • First, in silico screening — using computational docking of molecules into the PXR crystal structure — could be applied to the design of new combinatorial libraries and to aid in the selection of PXR-transparent building blocks.

  • Second, the development of high-throughput PXR binding assays would allow entire corporate compound collections to be screened. The identification of PXR ligands at this early stage of the drug discovery process will improve the likelihood that the undesired activity can be removed subsequently.

  • Third, PXR cell-based assays can be used during the process of lead optimization to ensure that clinical candidates are unlikely to induce CYP3A in vivo.

  • Last, humanized mice might prove useful in those cases in which the toxicology of PXR activation needs to be documented for risk assessment of human exposure.

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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Figure 1: Drug–drug interactions.
Figure 2: Cell-based reporter assays.
Figure 3: PXR and CAR ligands.
Figure 4: PXR and VDR ligand-binding domains.

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Correspondence to Timothy M. Willson.

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DATABASES

LocusLink

LocusLink

CAR

Car

CYP2B subfamily

Cyp2b

CYP3A subfamily

Cyp3a

CYP3A4

CYP4A

CYP27

glucocorticoid receptor

MDR1

MRP2

NR1I subfamily

OATP2

oestrogen receptor

PPARα

PXR

Pxr

RXR

thymidine kinase

vitamin D receptor

Medscape DrugInfo

chloropromazine

clotrimazole

cocaine

dexamethasone

gemfibrozil

phenobarbital

pioglitazone

ritonavir

rosiglitazone

taxol

taxotere

<I>Saccharomyces</I> Genome Database

Gal4

FURTHER INFORMATION

Encyclopedia of Life Sciences

pharmacogenetics

Washington University Mouse EST Database

Glossary

XENOBIOTICS

Molecules ingested in food, water or air, which include environmental toxins and synthetic drug molecules. Organisms have evolved a series of defence mechanisms to protect them from the harmful effects of xenobiotics. One of the primary mechanisms is oxidative metabolism, which occurs in the liver and intestine.

LIPOPHILIC

Literally, 'fat loving'. Applied to compounds (or parts of compounds) that have a tendency to dissolve in fat-like (for example, hydrocarbon) solvents. Lipophilic compounds will therefore accumulate in the lipid membrane of cells.

MONOOXYGENASE

An oxidoreductase enzyme that brings about the incorporation of one atom of oxygen (for example, as a part of a hydroxyl group) from O2 into a compound.

HEPATOMEGALY

Inflammation of the liver.

VAN DER WAALS INTERACTION

A van der Waals interaction is a weak attractive force that acts between non-bonded atoms or molecules. It accounts for the attraction of hydrophobic molecules to each other.

SCINTILLATION PROXIMITY ASSAY

Uses microscopic beads that contain a scintillant that can be stimulated to emit light. This stimulation event occurs only when radiolabelled molecules of interest are bound to the surface of the bead. A range of bead coatings allows bead types to be manufactured for specific applications, including screening for receptor–ligand binding, protein–protein interactions and protein–DNA interactions.

ANTIMYCOTIC

A substance that is used to kill a fungus or to inhibit its growth.

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Willson, T., Kliewer, S. Pxr, car and drug metabolism. Nat Rev Drug Discov 1, 259–266 (2002). https://doi.org/10.1038/nrd753

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