Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library

Lynch, Caitlin; Sakamuru, Srilatha; Huang, Ruili; Niebler, Jake; Ferguson, Stephen S. G.; Xia, Menghang

doi:10.1016/j.bcp.2020.114368

Cited by 20 publications

(14 citation statements)

References 48 publications

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“…transporter (Kostrubsky et al, 1998). The muscle relaxant, etomidoline, has been identified as a novel selective PXR agonist in a stable hPXR-Luc HepG2 cell line and up-regulated CYP3A4 mRNA expression in HepaRG cells in a PXR-dependent manner (Lynch et al, 2021). The calcium channel blockers, such as nifedipine, bendipine, and lacidipine, are used in the treatment of high blood pressure.…”

Section: Synthetic Drugsmentioning

confidence: 99%

“…The calcium channel blockers, such as nifedipine, bendipine, and lacidipine, are used in the treatment of high blood pressure. Studies have reported that these drugs are associated with hPXR activation (Bertilsson et al, 1998;Lynch et al, 2021). Several other drugs including carbamazepine (El-Sankary et al, 2001;), bosentan (van Giersbergen et al, 2002, mevastatin (Raucy et al, 2002), tamoxifen (Desai et al, 2002;Zhuo et al, 2014), topotecan (Schuetz et al, 2002) have all been reported to be activators of hPXR in cell-based reporter gene assays.…”

Section: Synthetic Drugsmentioning

confidence: 99%

“…Several other drugs including carbamazepine (El-Sankary et al, 2001;), bosentan (van Giersbergen et al, 2002, mevastatin (Raucy et al, 2002), tamoxifen (Desai et al, 2002;Zhuo et al, 2014), topotecan (Schuetz et al, 2002) have all been reported to be activators of hPXR in cell-based reporter gene assays. In addition, 11 additional drugs have recently been identified as novel hPXR activators (Lynch et al, 2021).…”

Section: Synthetic Drugsmentioning

confidence: 99%

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Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

2021

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It is well-known that the pregnane X receptor (PXR/Nr1i2) is a critical xenobiotic-sensing nuclear receptor enriched in liver and intestine and is responsible for drug-drug interactions (DDI), due to their versatile ligand binding domain (LBD) and target genes involved in xenobiotic biotransformation. PXR can be modulated by various xenobiotics including pharmaceuticals, nutraceuticals, dietary factors, and environmental chemicals. Microbial metabolites such as certain secondary bile acids (BAs) and the tryptophan metabolite indole-3-propionic acid (IPA) are endogenous PXR activators. Gut microbiome is increasingly recognized as an important regulator for host xenobiotic biotransformation and intermediary metabolism. PXR regulates and is regulated by the gut-liver axis. This review summarizes recent research advancements leveraging pharmaco-and toxico-metagenomic approaches that have redefined the previous understanding of PXR. Key topics covered in this review include 1) genome-wide investigations on novel PXR-target genes, novel PXR-DNA interaction patterns, and novel PXR-targeted intestinal bacteria; 2) key PXRmodulating activators and suppressors of exogenous and endogenous sources; 3) novel bidirectional interactions between PXR and gut microbiome under physiological, pathophysiological, pharmacological, and toxicological conditions; and 4) modifying factors of PXR-signaling including species-and sex difference, and time (age, critical windows of exposure, and circadian rhythm). The review also discusses critical knowledge gaps and important future research topics centering around PXR.

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Section: Synthetic Drugsmentioning

confidence: 99%

Section: Synthetic Drugsmentioning

confidence: 99%

Section: Synthetic Drugsmentioning

confidence: 99%

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Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

2021

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“…Ligand screening of PXR by high-throughput reporter assay-based methods is sometimes conducted to evaluate drug–drug interactions or chemical safety. For example, in the Tox21 project conducted by public research institutes in the United States, 10,000 chemicals were tested at 15 concentrations against a panel of nuclear receptors, including PXR, by reporter or one-hybrid assays ( 43 ). The reporter assay with PXR-F420A showed clear ligand-dependent activation and could be a suitable system for high-throughput screening of PXR ligands.…”

Section: Discussionmentioning

confidence: 99%

Helix 12 stabilization contributes to basal transcriptional activity of PXR

Shizu

Nishiguchi

Tashiro

et al. 2021

Journal of Biological Chemistry

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Pregnane X receptor (PXR) plays an important role in xenobiotic metabolism. While ligand binding induces PXR-dependent gene transcription, PXR shows constitutive transcriptional activity in the absence of ligands when expressed in cultured cells. This constitutive activity sometimes hampers investigation of PXR activation by compounds of interest. In this study, we investigated the molecular mechanism of PXR activation. In the reported crystal structures of unliganded PXR, helix 12 (H12), including a coactivator binding motif, was stabilized, while it is destabilized in the unliganded structures of other nuclear receptors, suggesting a role for H12 stabilization in the basal activity of PXR. Since Phe420, located in the loop between H11 and H12, is thought to interact with Leu411 and Ile414 to stabilize H12, we substituted alanine at Phe420 (PXR-F420A) and separately inserted three alanine residues directly after Phe420 (PXR-3A) and investigated their influence on PXR-mediated transcription. Reporter gene assays demonstrated that the mutants showed drastically reduced basal activity and enhanced responses to various ligands, which was further enhanced by coexpression of the coactivator peroxisome proliferator-activated receptor gamma coactivator 1α. Mutations of both Leu411 and Ile414 to alanine also suppressed basal activity. Mammalian two-hybrid assays showed that PXR-F420A and PXR-3A bound to corepressors and coactivators in the absence and presence of ligands, respectively. We conclude that the intramolecular interactions of Phe420 with Leu411 and Ile414 stabilize H12 to recruit coactivators even in the absence of ligands, contributing to the basal transcriptional activity of PXR. We propose that the generated mutants might be useful for PXR ligand screening.

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“…In addition, pregnane X receptor (PXR) is an upstream regulator of many metabolic enzymes and transporters. It plays a role in drug metabolism and detoxification by regulating the expression of downstream genes Cytochrome P450 3A4 (CYP3A4) [ 12 ]. Aromatic hydrocarbon receptor (AhR) is a nuclear and cytoplasmic shuttle protein, which can regulate the biochemical and toxicological reactions of environmental chemicals [ 13 ], and mainly mediates the expression regulation of the Cytochrome P450 1A1 (CYP1A1) and Cytochrome P450 1A2 (CYP1A2) genes [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Eurotium cristatum Fermented Loose Dark Tea and Eurotium cristatum Particle on MAPK and PXR/AhR Signaling Pathways Induced by Electronic Cigarette Exposure in Mice

Zhou

Liu

et al. 2022

Nutrients

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Electronic-cigarette smoke (eCS) has been shown to cause a degree of oxidative stress and inflammatory damage in lung tissue. The aim of this study was to evaluate the repair mechanism of Eurotium cristatum fermented loose dark tea (ECT) and Eurotium cristatum particle metabolites (ECP) sifted from ECT after eCS-induced injury in mice. Sixty C57BL/6 mice were randomly divided into a blank control group, an eCS model group, an eCS + 600 mg/kg ECP treatment group, an eCS + 600 mg/kg ECT treatment group, an eCS + 600 mg/kg ECP prevention group, and an eCS + 600 mg/kg ECT prevention group. The results show that ECP and ECT significantly reduced the eCS-induced oxidative stress and inflammation and improved histopathological changes in the lungs in mice with eCS-induced liver injury. Western blot analysis further revealed that ECP and ECT significantly inhibited the eCS-induced upregulation of the phosphorylation levels of the extracellular Regulated protein Kinases (ERK), c-Jun N-terminal kinase (JNK) and p38mitogen-activated protein kinases (p38MAPK) proteins, and significantly increased the eCS-induced downregulation of the expression levels of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) proteins. Conclusively, these findings show that ECP and ECT have a significant repairing effect on the damage caused by eCS exposure through the MAPK and PXR/AhR signaling pathways; ECT has a better effect on preventing eCS-induced injury and is suitable as a daily healthcare drink; ECP has a better therapeutic effect after eCS-induced injury, and might be a potential therapeutic candidate for the treatment of eCS-induced injury.

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Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library

Cited by 20 publications

References 48 publications

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

Helix 12 stabilization contributes to basal transcriptional activity of PXR

Protective Effect of Eurotium cristatum Fermented Loose Dark Tea and Eurotium cristatum Particle on MAPK and PXR/AhR Signaling Pathways Induced by Electronic Cigarette Exposure in Mice

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