A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism?

Wei, Yuan; Tang, Chenxiao; Sant, Vinayak; Li, Song; Poloyac, Samuel M.; Xie, Wen

doi:10.1007/s40495-016-0062-1

Cited by 23 publications

(19 citation statements)

References 55 publications

(74 reference statements)

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“…Many PXR-regulated metabolizing enzymes and transporters play critical roles in xenobiotic metabolism. For instance, PXR is the main regulator of CYP3A4 (Wei et al, 2016), the most abundant hepatic and intestinal phase I enzyme, which is responsible for metabolizing greater than 50% of clinically used drugs, along with many other xenobiotics and endobiotics, in humans (Harris et al, 2003). Furthermore, the expression of several of the aforementioned drug-metabolizing enzymes and transporters, in addition to that of at least 30 other genes, is under the control of the liganded PXR (Hariparsad et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

PXR: More Than Just a Master Xenobiotic Receptor

2017

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Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function. For instance, recent studies have discovered previously unidentified roles of PXR in inflammatory response, cell proliferation, and cell migration. PXR also contributes to the dysregulation of these processes in diseases states. These recent discoveries of the role of PXR in the physiologic and pathophysiologic conditions of other cellular processes provides the possibility of novel targets for drug discovery. This review highlights areas of PXR regulation that require further clarification and summarizes the recent progress in our understanding of the nonxenobiotic functions of PXR that can be explored for relevant therapeutic applications.

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Section: Introductionmentioning

confidence: 99%

PXR: More Than Just a Master Xenobiotic Receptor

2017

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“…However, no systematic algorithm or widely accepted predictive model to evaluate, quantify, and eliminate DDIs have been developed so far. Since many PXR ligands can also function as reversible or irreversible inhibitors of CYPs, the overall effects of PXR ligands should be considered with respect to DDIs, which challenges us to build a suitable quantitative model of DDIs [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Tebbens

Azar

Friedmann

et al. 2018

IJMS

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The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug–drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.

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“…The AhR is mainly involved in the induction of CYP1A isoforms (see [11]). Inhibition mainly concerns metabolic enzymes and can be generally divided into three categories: reversible, quasi-irreversible and irreversible inhibition (see [12]). The reversible inhibition is involved in drug interactions and occurs between the competition for CYP binding site between substrate drugs and inhibitors.…”

Section: Mechanisms Of Action Of Herbal Medicines-drugs Interactionsmentioning

confidence: 99%

“…The reversible inhibition is involved in drug interactions and occurs between the competition for CYP binding site between substrate drugs and inhibitors. Reversible inhibition can be further divided into competitive, non-competitive, uncompetitive, and mixed-type inhibition (see [12]). In particular, competitive or non-competitive inhibition is mainly involved in interactions between herbal medicines and drugs.…”

Section: Mechanisms Of Action Of Herbal Medicines-drugs Interactionsmentioning

confidence: 99%

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Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance

Rombolà

Scuteri

Straface

et al. 2020

Life

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The therapeutic efficacy of a drug or its unexpected unwanted side effects may depend on the concurrent use of a medicinal plant. In particular, constituents in the medicinal plant extracts may influence drug bioavailability, metabolism and half-life, leading to drug toxicity or failure to obtain a therapeutic response. This narrative review focuses on clinical studies improving knowledge on the ability of selected herbal medicines to influence the pharmacokinetics of co-administered drugs. Moreover, in vitro studies are useful to anticipate potential herbal medicine-drug interactions. In particular, they help to elucidate the cellular target (metabolic or transporter protein) and the mechanism (induction or inhibition) by which a single constituent of the herbal medicine acts. The authors highlight the difficulties in predicting herbal–drug interactions from in vitro data where high concentrations of extracts or their constituents are used and pharmacokinetics are missed. Moreover, the difficulty to compare results from human studies where different kinds of herbal extracts are used is discussed. The herbal medicines discussed are among the best sellers and they are reported in the “Herbal Medicines for Human Use” section of the European Medicinal Agency (EMA).

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A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism?

Cited by 23 publications

References 55 publications

PXR: More Than Just a Master Xenobiotic Receptor

PXR: More Than Just a Master Xenobiotic Receptor

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance

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