scholarly journals Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3381
Author(s):  
Zhihui Li ◽  
Linhao Li ◽  
Scott Heyward ◽  
Shuaiqian Men ◽  
Meishu Xu ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Luciferase Reporter ◽  
Primary Hepatocytes ◽  
Metabolizing Enzymes ◽  
Potent Inducer ◽  
Citrate Transporter ◽  
Heparg Cells ◽  
Mrna And Protein Expression ◽  
Human Primary Hepatocytes

Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.

scholarly journals The Nuclear Receptor PXR in Chronic Liver Disease

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 61
Author(s):  
Katia Sayaf ◽  
Ilaria Zanotto ◽  
Francesco Paolo Russo ◽  
Daniela Gabbia ◽  
Sara De Martin
Keyword(s):  
Nuclear Receptor ◽  
Liver Diseases ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Chronic Liver ◽  
Cytochrome P450 3A4 ◽  
Chronic Liver Diseases ◽  
Metabolizing Enzymes ◽  
P Glycoprotein ◽  
And Function

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.

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

2018 ◽  
Vol 19 (11) ◽  
pp. 3630 ◽  
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.

Cellular impact of combinations of endosulfan, atrazine, and chlorpyrifos on human primary hepatocytes and HepaRG cells after short and chronic exposures

2013 ◽  
Vol 30 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Ahmad Nawaz ◽  
Andrej Razpotnik ◽  
Patrick Rouimi ◽  
Georges de Sousa ◽  
Jean Pierre Cravedi ◽  
...  
Keyword(s):  
Primary Hepatocytes ◽  
Heparg Cells ◽  
Human Primary Hepatocytes

Different Induction Effects of Praziquantel Racemate and Enantiomers on the Enzyme CYP3A4 Mediated by Pregnane X Receptor and Its Variants

2021 ◽  
Vol 21 ◽  
Author(s):  
Ran Meng ◽  
Xueli Zhang ◽  
Haina Wang ◽  
Danlu Zhang ◽  
Xin Zhao
Keyword(s):  
Hepg2 Cells ◽  
Pregnane X Receptor ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Luciferase Reporter Gene ◽  
Concentration Dependent Manner ◽  
Protein Levels ◽  
Mrna And Protein Expression ◽  
Polymerase Chain ◽  
Expression Plasmids

Background: Praziquantel (PZQ), which possesses an asymmetric center, is classified as a pyrazinoisoquinoline and has been the mainstay in the treatment of schistosomiasis since 1980. PZQ undergoes a pronounced first-pass metabolism in the liver through the CYP450 system which could be mediated by nuclear receptors. Objective: The purpose of this study was to investigate the possible different induction effects of CYP3A4 by PZQ racemate and enantiomers via the pregnane X receptor (PXR) and the effect of PXR polymorphism on the induction potency of PZQs. Methods: The dual-luciferase reporter gene systems constructed in HepG2 cells were used to measure the abilities of PZQs to induce CYP3A4 expression mediated by PXR. The mRNA and protein levels of CYP3A4 were evaluated by polymerase chain reaction (PCR) and western blotting, respectively. Results: In HepG2 cells transfected with PXRwt, PXR158, PXR163, PXR370 or PXR403 expression plasmids, PZQ racemate and its enantiomers up-regulated the luciferase activity in a concentration-dependent manner, while reaching saturation after transfected with PXR379 expression plasmids. The mRNA and protein expression of CYP3A4 was effectively activated in PXR-transfected HepG2 cells. The induction ability of CYP3A4 mediated by PXR activation by PZQ racemate and its enantiomers were statistically different between the same PXR group and different PXR groups. Conclusion: The enantioselective induction effects of PZQs on CYP3A4 were related to the enantioselective activations of PXR by PZQs and were influenced by the PXR gene polymorphism. These findings provide a basis for further understanding the enantiomeric metabolism and the variable efficacy of PZQs.

Differential Effects of Components in Artemisia annua Extract on the Induction of Drug-Metabolizing Enzyme Expression Mediated by Nuclear Receptors

Planta Medica ◽  
2020 ◽  
Vol 86 (12) ◽  
pp. 867-875
Author(s):  
Xueli Zhang ◽  
Ran Meng ◽  
Haina Wang ◽  
Jie Xing
Keyword(s):  
Reporter Gene ◽  
Artemisia Annua ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Luciferase Reporter ◽  
Induction Effect ◽  
Luciferase Reporter Gene ◽  
Gene System ◽  
Drug Metabolizing Enzyme ◽  
Reporter Gene System

Abstract Artemisia annua tea is a popular dosage form used to treat and prevent malaria in some developing countries. However, repeated drinking leads to an obviously decreased efficacy, which may be related to the induction of metabolizing enzymes by artemisinin. In the present study, the ability of different components in A. annua to activate the pregnane X receptor and constitutive androstane receptor was evaluated by the dual luciferase reporter gene system. The changes in mRNA and protein expression of CYP3A4 and CYP2B6 were determined by quantitative real-time PCR and Western blotting. Results showed that in the pregnane X receptor-mediated CYP3A4 reporter gene system, chrysosplenetin and arteannuin B exhibited a weak induction effect on pregnane X receptor wt, while arteannuin A had a strong induction effect on pregnane X receptor wt and pregnane X receptor 370 and a weak induction effect on pregnane X receptor 163. In the pregnane X receptor-mediated CYP2B6 reporter gene system, arteannuin A had a moderate induction effect on pregnane X receptor wt and pregnane X receptor 379, and a weak induction effect on pregnane X receptor 403, while arteannuin B had a weak induction effect on pregnane X receptor wt and pregnane X receptor 379. Arteannuin A had a strong induction effect on constitutive androstane receptor 3 in constitutive androstane receptor-mediated CYP3A4/2B6 reporter gene systems, while arteannuin B showed a weak induction effect on constitutive androstane receptor 3 in the constitutive androstane receptor-mediated CYP2B6 reporter gene system. The mRNA and protein expressions of CYP3A4 and CYP2B6 were increased when the pregnane X receptor or constitutive androstane receptor was activated. Various components present in A. annua differentially affect the activities of pregnane X receptor isoforms and the constitutive androstane receptor, which indicates the possibility of a drug-drug interaction. This partly explains the decline in efficacy after repeated drinking of A. annua tea.

Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes

Xenobiotica ◽  
2004 ◽  
Vol 34 (7) ◽  
pp. 619-632 ◽  
Author(s):  
K. Gross-Steinmeyer ◽  
P. L. Stapleton ◽  
F. Liu ◽  
J. H. Tracy ◽  
T. K. Bammler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Primary Hepatocytes ◽  
Metabolizing Enzymes ◽  
Human Primary Hepatocytes ◽  
Induced Changes
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