Targeting the pregnane X receptor in liver injury

Introduction: The nuclear receptor pregnane X receptor (PXR) is a well-characterized hepatic xenobiotic sensor whose activation by chemically diverse compounds results in the induction of drug clearance pathways that rid the body of potentially toxic substances, thus conferring protection from foreign chemicals and endobiotics.

Areas covered: PXR activities are implicated in drug–drug interactions and endocrine disruption. Recent evidence supports a hepatoprotective role for PXR in chronic liver injury, inhibiting liver inflammation through suppression of the NF-κB pathway. However, PXR-mediated induction of CYP3A enhances APAP-induced acute liver injury by generating toxic metabolites. While these observations implicate PXR as a therapeutic target for liver injury, they also caution against PXR activation by pharmaceutical drugs.

Expert opinion: While evidence of PXR involvement in acute and chronic liver injuries identifies it as a possible therapeutic target, it raises additional concerns for all drug candidates. The in vitro and in vivo tests for human PXR activation should be incorporated into the FDA regulations for therapeutic drug approval to identify potential liver toxicities. In addition, PXR pharmacogenetic studies will facilitate the prediction of patient-specific drug reactivities and associated liver disorders.     

Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes

During the past several years, important advances have been made in our understanding of the mechanisms that regulate the expression of genes that determine drug clearance, including phase I and phase II drug-metabolising enzymes and drug transporters. Orphan nuclear receptors have been recognised as key mediators of drug-induced changes in both metabolism and efflux mechanisms. In this review, we summarise recent findings regarding the function of nuclear receptors in regulating drug-metabolising and transport systems, and the relevance of these receptors to clinical drug-drug interactions and the development of new drugs. Emphasis is given to two newly recognised 'orphan' receptors (the pregnane X receptor [PXR] and the constitutive androstane receptor [CAR]) and their regulation of cytochrome P450 enzymes, such as CYP3A4, CYP2Cs and CYP2B6; and transporters, such as P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs) and organic anion transporter peptide 2 (OATP2). Although 'cross-talk' occurs between these two receptors and their target sequences, significant species differences exist between ligand-binding and activation profiles for both receptors, and PXR appears to be the predominant or 'master' regulator of hepatic drug disposition in humans. Several important physiological processes, such as cholesterol synthesis and bile acid metabolism, are also tightly controlled by certain ligand-activated orphan nuclear receptors (farnesoid X receptor [FXR] and liver X receptor [LXR]). In general, their ability to bind a broad range of ligands and regulate an extensive array of genes that are involved in drug clearance and disposition makes these orphan receptors attractive targets for drug development. Drugs have the capacity to alter nuclear receptor expression (modulators) and/or serve as ligands for the receptors (agonists or antagonists), and thus can have synergistic or antagonistic effects on the expression of drug-metabolising enzymes and transporters. Coadministration of drugs that are nuclear receptor agonists or antagonists can lead to severe toxicity, a loss of therapeutic efficacy or an imbalance in physiological substrates, providing a novel molecular mechanism for drug-drug interactions.     

Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk

Introduction: Protein-protein interaction and signaling crosstalk contribute to the regulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and broaden their cellular function.

Area covered: This review covers key historic discoveries and recent advances in our understanding of the broad function of PXR and CAR and their regulation by protein-protein interaction and signaling crosstalk.

Expert opinion: PXR and CAR were first discovered as xenobiotic receptors; however, it is clear that PXR and CAR perform a much broader range of cellular functions through protein-protein interaction and signaling crosstalk, which typically mutually affect the function of all the partners involved. Future research on PXR and CAR should, therefore, look beyond their xenobiotic function.     

中草药对孕烷X受体和组成型雄烷受体等核受体通路影响的研究进展

孕烷X受体（pregnane X receptor,PXR）是核受体亚家族的成员之一,参与大量的外源性和内源性化学物质的生物转化,能被多种中草药激活,调节下游靶基因的表达,在药物代谢酶和转运体的调节中起重要作用。组成型雄烷受体（constitutive androstane receptor,CAR）和PXR一样能与外源性配体结合调节CYP2B6、CYP3A4、CYP2C19、UGT1A1的表达,共同参与CYP药物代谢酶的调节,成为药物作用的靶标。     

孕烷X受体生物特性及其在药物代谢中的作用研究进展

核受体孕烷X受体是一类生物体内广泛分布的激素和环境感受器,不仅可参与能量、胆固醇、胆汁酸等物质的代谢以及调节炎症反应,还可以调控工相、Ⅱ相药物代谢酶和相关药物转运蛋白的表达而调节药物代谢,其作用对维持机体诸如细胞增殖分化、生长发育、新陈代谢、稳态维持等多种生理功能有重要意义。本文就孕烷x受体结构功能、生物学效应以及其对药物代谢酶和药物转运调节的作用等作一综述。     

The importance of drug transporters in human pluripotent stem cells and in early tissue differentiation

Introduction: Drug transporters are large transmembrane proteins which catalyse the movement of a wide variety of chemicals, including drugs as well as xeno- and endobiotics through cellular membranes. The major groups of these proteins include the ATP-binding cassette transporters which in eukaryotes work as ATP-fuelled drug ‘exporters’ and the Solute Carrier transporters, with various transport directions and mechanisms.

Areas covered: In this review, we discuss the key ATP-binding cassette and Solute Carrier drug transporters which have been reported to contribute to the function and/or protection of undifferentiated human stem cells and during tissue differentiation. We review the various techniques for studying transporter expression and function in stem cells, and the role of drug transporters in foetal and placental tissues is also discussed. We especially focus on the regulation of transporter expression by factors modulating cell differentiation properties and on the function of the transporters in adjustment to environmental challenges.

Expert opinion: The relatively new and as yet unexplored territory of transporters in stem cell biology may rapidly expand and bring important new information regarding the metabolic and epigenetic regulation of ‘stemness’ and the early differentiation properties. Drug transporters are clearly important protective and regulatory components in stem cells and differentiation.     

Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor

Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors suggests that these proteins evolved to an integrated biotransformation system. Two major groups of ligand-activated nuclear receptors/xenosensors evolved: the Ah receptor (activated by aryl hydrocarbons and drugs such as omeprazole) and type 2 steroid receptors such as PXR and CAR, activated by drugs such as rifampicin, carbamazepin and phenytoin. It is increasingly recognized that there is considerable cross-talk between these xenosensors. Therefore, an attempt was made to discuss biotransformation by the Ah receptor together with that of PXR and CAR. Due to considerable species differences the emphasis is on human biotransformation. Agonists coordinately induce biotransformation due to common xenosensor-binding response elements in the regulatory region of target genes. However, whereas different groups of xenobiotics appear to more selectively stimulate CYPs (Phase I), their regulatory control largely converged in modulating Phase II metabolism and transport. Biotransformation appears to be tightly controlled to achieve efficient homeostasis of endobiotics and detoxification of dietary phytochemicals, but nuclear receptor agonists may also lead to potentially harmful drug interactions.     

孕烷X受体介导的代谢酶和转运体转录调控及其在化疗药物耐药中的作用

孕烷X受体(PXR,NR1I2)是生物体内药物代谢酶和转运体基因表达的主要调控因子之一.近来研究发现,PXR介导的药物代谢酶和转运体的过表达,与化疗药物多药耐药的产生密切相关.鉴于PXR在药物代谢酶和转运体调控中的重要性和PXR转录调控的多样性,有必要对其导致的多药耐药形成机制进行更深入的研究.本文综述了PXR介导的代谢酶和转运体基因表达调控机制,及其引起化疗药物多药耐药的相关研究进展,为提高化疗药物敏感性、逆转化疗药物的多药耐药提供有效的治疗策略.     

Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs

Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. An important determinant of such interindividual differences in drug response is variability in the expression of drug-metabolizing enzymes and/or transporters at sites of absorption and/or tissue distribution. Variable drug-metabolizing enzyme and transporter expression can result in unpredictable exposure and tissue distribution of drugs and may manifest as adverse effects or therapeutic failure. In the past decade, important new insights have been made relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. Specifically, there is compelling evidence to demonstrate that PXR, CAR, FXR, LXR, VDR, HNF4alpha, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzyme and transporters. In this review, the authors focus on clinically important drug-metabolizing enzymes such as CYP3A4, CYP2B6, CYP2C9, CYP2C19, UGT1A1, SULT2A1, and glutathione S-transferases and their regulation by nuclear receptors. They also review the nuclear receptor-mediated regulation of drug transporters such as MDR1, MRP2, MRP4, BSEP, BCRP, NTCP, OATP1B3, and OATP1A2. Finally, they outline how the drug development process has been affected by the current understanding of the involvement of nuclear receptors in the regulation of drug disposition genes.     

Emerging concepts and approaches for chemokine-receptor drug discovery

Importance of the field: Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.

Areas covered in this review: Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.

What the reader will gain: Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.

Take home message: Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil^? for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.     

A current structural perspective on PXR and CAR in drug metabolism

Introduction: Pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that play major roles in the expression of various drug metabolism enzymes and are known for their ligand promiscuity. As with other nuclear receptors, PXR and CAR are each composed of a ligand-binding domain (LBD) and a DNA-binding domain (DBD) connected by a hinge region.

Areas covered: This review focuses on the information obtained over the last 15+ years from X-ray crystallography studies of the structure of PXR and CAR. Areas of focus include the mobility of each structure, based on temperature factors (B factors); multimeric interactions; the binding of coregulators and ligands; and how the crystal structures were obtained. The first use of hydrogen-deuterium exchange coupled with mass spectroscopy (HDX-MS) to study compound-protein interactions in the PXR-LBD is also addressed.

Expert opinion: X-ray crystallography studies have provided us with an excellent understanding of how the LBDs of each receptor function; however, many questions remain concerning the structure of these receptors. Future research should focus on determining the co-crystal structure of an antagonist bound to PXR and on studying the structural aspects of the full-length CAR and PXR proteins.