Pregnane X receptor and drug-induced liver injury

Wang, Yueming; Chai, Sergio C.; Brewer, Christopher T.; Chen, Taosheng

doi:10.1517/17425255.2014.963555

Cited by 50 publications

(37 citation statements)

References 124 publications

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“…Genetic polymorphisms in the pregnane X receptor (PXR) gene have been examined in several studies as potential risk factors for AT-DILI [82–84]. A study that examined genotypes and haplotypes with six SNPs in the PXR gene in female Chinese populations found associations between PXR genetic polymorphisms (rs2461823 and rs7643645) and increased risk of AT-DILI [82].…”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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Purpose of this Review In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

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Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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“…Unlike the ligand cavity of most NRs, the binding pocket of PXR is prominent for being large and highly flexible, which enables it to accommodate ligands of great diversity in terms of their chemical scaffold, size, lipophilicity, and surface area . Figure shows reported modulators of PXR in a manner that illustrates the large chemical space that they encompass, thus providing an impression of the extensive range of their physiochemical properties. Most of the chemicals recognized by the ligand‐binding pocket result in PXR activation, and this agonistic promiscuity is a major impediment to the development of PXR antagonists.…”

Section: Current Status Of Pxr Antagonist Development Challenges Anmentioning

confidence: 99%

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

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“…These 5 mechanisms have a demonstrable association to increased risk for clinical hepatotoxicity. 20–24 …”

Section: In Vitro Models For Predicting Drug-induced Hepatotoxicitymentioning

confidence: 99%

Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy

Vernetti

Vogt

Gough

et al. 2017

Clinics in Liver Disease

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In this article, we review the past applications of in vitro models in identifying human hepatotoxins and then focus on the use of multiscale experimental models in drug development, including the use of zebrafish and human cell-based, 3-dimensional, microfluidic systems of liver functions as key components in applying Quantitative Systems Pharmacology (QSP). We have implemented QSP as a platform to improve the rate of success in the process of drug discovery and development of therapeutics.

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Pregnane X receptor and drug-induced liver injury

Cited by 50 publications

References 124 publications

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy

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