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

Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

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Sesquiterpenes Are Agonists of the Pregnane X Receptor but Do Not Induce the Expression of Phase I Drug-Metabolizing Enzymes in the Human Liver

International Journal of Molecular Sciences ◽

10.3390/ijms20184562 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4562

Author(s):

Michaela Šadibolová ◽

Tomáš Zárybnický ◽

Tomáš Smutný ◽

Petr Pávek ◽

Zdeněk Šubrt ◽

...

Keyword(s):

Cytochrome P450 ◽

Phase I ◽

Reporter Gene ◽

Pregnane X Receptor ◽

Receptor Interaction ◽

Cytochrome P450 3A4 ◽

Drug Metabolizing Enzymes ◽

Metabolizing Enzymes ◽

Protein Levels ◽

Reporter Gene Assays

Sesquiterpenes, the main components of plant essential oils, are bioactive compounds with numerous health-beneficial activities. Sesquiterpenes can interact with concomitantly administered drugs due to the modulation of drug-metabolizing enzymes (DMEs). The aim of this study was to evaluate the modulatory effects of six sesquiterpenes (farnesol, cis-nerolidol, trans-nerolidol, α-humulene, β-caryophyllene, and caryophyllene oxide) on the expression of four phase I DMEs (cytochrome P450 3A4 and 2C, carbonyl reductase 1, and aldo-keto reductase 1C) at both the mRNA and protein levels. For this purpose, human precision-cut liver slices (PCLS) prepared from 10 patients and transfected HepG2 cells were used. Western blotting, quantitative real-time PCR and reporter gene assays were employed in the analyses. In the reporter gene assays, all sesquiterpenes significantly induced cytochrome P450 3A4 expression via pregnane X receptor interaction. However in PCLS, their effects on the expression of all the tested DMEs at the mRNA and protein levels were mild or none. High inter-individual variabilities in the basal levels as well as in modulatory efficacy of the tested sesquiterpenes were observed, indicating a high probability of marked differences in the effects of these compounds among the general population. Nevertheless, it seems unlikely that the studied sesquiterpenes would remarkably influence the bioavailability and efficacy of concomitantly administered drugs.

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Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19113630 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3630 ◽

Cited By ~ 11

Author(s):

Manon Garcia ◽

Laura Thirouard ◽

Lauriane Sedès ◽

Mélusine Monrose ◽

Hélène Holota ◽

...

Keyword(s):

Transcriptional Control ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Nuclear Hormone Receptor ◽

Farnesoid X Receptor ◽

Metabolizing Enzymes ◽

Functional Studies ◽

Endogenous Metabolites ◽

Pathologic Processes

Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.

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Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

Biomolecules ◽

10.3390/biom11081142 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1142

Author(s):

Aikaterini Skandalaki ◽

Panagiotis Sarantis ◽

Stamatios Theocharis

Keyword(s):

Personalized Medicine ◽

Nuclear Receptors ◽

Antineoplastic Agents ◽

Pregnane X Receptor ◽

Chemotherapeutic Agents ◽

Drug Metabolizing Enzymes ◽

Chemotherapeutic Drugs ◽

Metabolizing Enzymes ◽

And Personalized Medicine ◽

Selection Of

Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.

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