Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CARā
Introduction
Exposure to xenobiotics such as drugs and environmental chemicals has profound influence on human health. In order to modulate their own metabolism and excretion, xenobiotics alter the transcription of a broad array of genes expressed in multiple tissues and vital organs such as the liver, kidney, intestine, lungs, brain, placenta, and pancreas [1], [2], [3]. Mechanistically speaking however, it is majorly the mammalian nuclear receptor (NR) superfamily of transcription factors that makes xenobiotic regulation of gene expression at the transcriptional level possible. The characteristic structural features of NRs include a highly-conserved DNA-binding domain (DBD), which links the receptors to specific promoter regions of their target genes, and a less conserved ligand-binding domain (LBD) that permits them to directly interact with hormones and/or xenobiotics [4], [5]. Moreover, the extraordinary flexibility in the size and shape of LBDs provides the basis for a number of NRs being able to accommodate a myriad of ligands with diverse chemical structuresĀ [6], [7]. Notably, the first human nuclear receptor, glucocorticoid receptor (GR), was cloned starting from the purification and characterization of the receptor protein from the cortisone-producing adrenal glands, before specific antibodies were used to isolate the corresponding cDNA [8], [9]. Utilizing these classical endocrinology approaches, a number of endocrine receptors such as GR, estrogen receptor (ER), and thyroid hormone receptor (TR), were isolated soon thereafter. Typically all these receptors have relatively compact LDBs and are capable of binding unique high-affinity endogenous ligands at nanomolar concentrations.
Taking advantage of the fact that nearly all NRs share a highly conserved cysteine-rich DBD, researchers strive to search for unrecognized NRs using this common segment as bait to screen recombinant DNA libraries at low stringency [10]. This approach has led to the identification of a group of proteins that resemble NRs on the basis of structure and sequence, but lack identified endogenous ligands. Coined āorphan receptors,ā this group of NRs accounts for approximately 60% of the over 70 distinct members of the NR superfamily [11], [12], [13]. The availability of this large number of orphan receptors also triggered a shift of the classic endocrinology approach into the so called āreverse endocrinologyā one, whereby instead of using a purified hormone to identify its partner receptor, novel bioactive molecules were recognized as selective ligands of these orphan receptors [14]. As such, a number of the orphan receptors were termed āadopted.ā Nevertheless, in contrast to the prototypical endocrine receptors, members of the orphan receptors are typically activated by abundant but low-affinity lipophilic molecules at micromolar concentrations [15], [16].
Notably, the majority of ligands for orphan or adopted receptors are xenobiotics including drugs, carcinogens, food additives, pesticides and environmental pollutants [17]. Functioning as sensors of toxic byproducts derived from both endogenous and exogenous chemical breakdowns, a number of these receptors were also termed xenobiotic receptors, which include but are not limited to: farnesoid X receptor (FXR), liver X receptor (LXR), proxisome proliferator activation receptors (PPARs), constitutive androstane/active receptor (CAR), pregnane X receptor (PXR), nuclear factor-erythroid 2-related factor 2 (Nrf2), and aryl hydrocarbon receptor (AhR). Also worth mentioning, though primarily responsive to xenobiotics, AhR belongs to the basic helixāloopāhelix protein of the PAS Per-ARNT-Sim (PAS) family, not to the NR superfamily [18]. Among these xenobiotic receptors, PXR and CAR exhibit promiscuous xenobiotic activation capability; and collaboratively they govern the transcription of a broad spectrum of distinct and overlapping genes encoding phase I, phase II drug-metabolizing enzymes (DMEs), as well as uptake and efflux transporters [17], [19], [20], [21], [22] (Fig.Ā 1).
The purpose of this review is to highlight the recent advances in our understanding of the regulation of DMEs and transporters by xenobiotic receptors: PXR and CAR. Emphasis is given to the distinct, rather than the overlapping roles, of PXR and CAR in gene regulation. To a lesser extent, we also discuss the role of AhR as a xenosensor. This review however is by no means a comprehensive coverage of CAR, PXR, and AhR research findings.
Section snippets
Pregnane X receptor (PXR)
The pregnane X receptor (PXR, NR1I2) is an approximately 434-amino acid, 50-kDa protein, primarily expressed in the liver and intestine [23]. In 1998, three research groups independently isolated cDNAs encoding a novel orphan receptor, PXR, which was subsequently shown to play a central role in the transcriptional regulation of CYP3A genes across multiple species [24], [25], [26]. Prior to being designated NR1I2, this receptor was also named SXR (steroid and xenobiotic receptor) and PAR
Constitutive androstane/activated receptor (CAR)
In the nuclear receptor superfamily tree, CAR (NR1I3) is the closest relative to the abovementioned PXR and is expressed primarily in the liver and intestine. Initially named MB67 in 1994, this receptor was designated as constitutive activated receptor (CAR), because it forms a heterodimer with retinoid X receptor (RXR) that binds to retinoic acid response elements (RAREs) and transactivates target genes in the absence of ligand stimulation [105], [106]. In 1998, the first class of CAR ligands
Aryl hydrocarbon receptor (AhR)
In addition to PXR and CAR, a ligand-activated transcription factor AhR has been frequently referred to as another important xenosensor dictating the inductive expression of many DMEs and transporters. Although AhR was classified into the basic helixāloopāhelix protein of the PER-ARNT-SIM (PAS) family, it shares several important characteristics comparable to CAR and PXR as xenobiotic receptors [18], [141]. In response to chemical activation, AhR enhances the expression of drug-metabolizing
Concluding remarks
Over the past ten years, remarkable advances have been achieved in our understanding of CAR and PXR-governed inductive expression of drug metabolism and disposition genes. It is clear now that, as the major xenobiotic receptors, CAR and PXR control a largely overlapping array of genes coding hepatic DMEs and transporters, thereby affecting the pharmacokinetics and toxicity of many drugs and environmental chemicals. The impact of these xenobiotic receptors on the induction-related DDIs has been
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This review is part of the Advanced Drug Delivery Reviews theme issue on āDevelopment of Novel Therapeutic Strategy by Regulating the Nuclear Hormone Receptorsā.