scholarly journals Pregnane X Receptor and Constitutive Androstane Receptor at the Crossroads of Drug Metabolism and Energy Metabolism

2010 ◽  
Vol 38 (12) ◽  
pp. 2091-2095 ◽  
Author(s):  
Jie Gao ◽  
Wen Xie
Keyword(s):  
Energy Metabolism ◽  
Drug Metabolism ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor

scholarly journals Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library

2018 ◽  
Vol 167 (1) ◽  
pp. 282-292 ◽  
Author(s):  
Caitlin Lynch ◽  
Bryan Mackowiak ◽  
Ruili Huang ◽  
Linhao Li ◽  
Scott Heyward ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Therapy ◽  
Drug Metabolism ◽  
Drug Interactions ◽  
Tumor Progression ◽  
Nuclear Receptor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Compound Library ◽  
Compound Collection

Abstract The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it’s been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister receptor, the pregnane X receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.

Regulatory Cross-Talk between Drug Metabolism and Lipid Homeostasis: Constitutive Androstane Receptor and Pregnane X Receptor Increase Insig-1 Expression

2008 ◽  
Vol 73 (4) ◽  
pp. 1282-1289 ◽  
Author(s):  
Adrian Roth ◽  
Renate Looser ◽  
Michel Kaufmann ◽  
Sharon M. Blättler ◽  
Franck Rencurel ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Cross Talk ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Lipid Homeostasis

The Role of Xenobiotic Receptors on Hepatic Glycolipid Metabolism

2019 ◽  
Vol 20 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Ke Chen ◽  
Jinwei Zhong ◽  
Lin Hu ◽  
Ruliu Li ◽  
Qun Du ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Energy Metabolism ◽  
Constitutive Androstane Receptor ◽  
Main Idea ◽  
Pregnane X Receptor ◽  
Research Literature ◽  
Negative Regulator ◽  
Glucose And Lipid Metabolism ◽  
Obesity And Diabetes ◽  
Hepatic Glucose

Background: PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) are termed as xenobiotic receptors, which are known as core factors in regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis and β-oxidation. Therefore, in this review, we are trying to summary recent advances to show how xenobiotic receptors regulate energy metabolism. Methods: A structured search of databases has been performed by using focused review topics. According to conceptual framework, the main idea of research literature was summarized and presented. Results: For introduction of each receptor, the general introduction and the critical functions in hepatic glucose and lipid metabolism have been included. Recent important studies have shown that CAR acts as a negative regulator of lipogenesis, gluconeogenesis and β -oxidation. PXR activation induces lipogenesis, inhibits gluconeogenesis and inhabits β-oxidation. Conclusion: In this review, the importance of xenobiotic receptors in hepatic glucose and lipid metabolism has been confirmed. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. However, further research is required to promote the clinical application of this new energy metabolism function of xenobiotic receptors.

scholarly journals Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis

2019 ◽  
Vol 51 (2) ◽  
pp. 226-235 ◽  
Author(s):  
Daisuke Uehara ◽  
Hiroki Tojima ◽  
Satoru Kakizaki ◽  
Yuichi Yamazaki ◽  
Norio Horiguchi ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor

scholarly journals Evolutionary Plasticity in Detoxification Gene Modules: The Preservation and Loss of the Pregnane X Receptor in Chondrichthyes Lineages

2019 ◽  
Vol 20 (9) ◽  
pp. 2331 ◽  
Author(s):  
Elza S. S. Fonseca ◽  
Raquel Ruivo ◽  
André M. Machado ◽  
Francisca Conrado ◽  
Boon-Hui Tay ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Gene Families ◽  
Critical Question ◽  
Group I ◽  
Activation Profile ◽  
Gene Duplication And Loss ◽  
Molecular Landscape ◽  
Gene Orthologs

To appraise how evolutionary processes, such as gene duplication and loss, influence an organism’s xenobiotic sensitivity is a critical question in toxicology. Of particular importance are gene families involved in the mediation of detoxification responses, such as members of the nuclear receptor subfamily 1 group I (NR1I), the pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). While documented in multiple vertebrate genomes, PXR and CAR display an intriguing gene distribution. PXR is absent in birds and reptiles, while CAR shows a tetrapod-specific occurrence. More elusive is the presence of PXR and CAR gene orthologs in early branching and ecologically-important Chondrichthyes (chimaeras, sharks and rays). Therefore, we investigated various genome projects and use them to provide the first identification and functional characterization of a Chondrichthyan PXR from the chimaera elephant shark (Callorhinchus milii, Holocephali). Additionally, we substantiate the targeted PXR gene loss in Elasmobranchii (sharks and rays). Compared to other vertebrate groups, the chimaera PXR ortholog displays a diverse expression pattern (skin and gills) and a unique activation profile by classical xenobiotic ligands. Our findings provide insights into the molecular landscape of detoxification mechanisms and suggest lineage-specific adaptations in response to xenobiotics in gnathostome evolution.

scholarly journals Comparison of the Hepatic Effects of Phenobarbital in Chimeric Mice Containing Either Rat or Human Hepatocytes With Humanized Constitutive Androstane Receptor and Pregnane X Receptor Mice

2020 ◽  
Vol 177 (2) ◽  
pp. 362-376
Author(s):  
Tomoya Yamada ◽  
Ayako Ohara ◽  
Naoya Ozawa ◽  
Keiko Maeda ◽  
Miwa Kondo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Tumor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Rat Hepatocytes ◽  
Global Gene Expression ◽  
Human Hepatocytes ◽  
Chimeric Mouse ◽  
Chimeric Mice ◽  
Wild Type

Abstract Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, because rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild-type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/β-catenin signaling when compared with those of hCAR/hPXR mice, wild-type mice, and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators whereas the hCAR/hPXR mouse is not.

scholarly journals Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Céline Lukowicz ◽  
Sandrine Ellero-Simatos ◽  
Marion Régnier ◽  
Fabiana Oliviero ◽  
Frédéric Lasserre ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Hepatic Steatosis ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Constitutive Androstane Receptor ◽  
Developed Countries ◽  
Health Concern ◽  
Endocrine Disorders ◽  
Male Mice ◽  
Treatment Of Obesity

AbstractMetabolic diseases such as obesity, type II diabetes and hepatic steatosis are a public health concern in developed countries. The metabolic risk is gender‐dependent. The constitutive androstane receptor (CAR), which is at the crossroads between energy metabolism and endocrinology, has recently emerged as a promising therapeutic agent for the treatment of obesity and type 2 diabetes. In this study we sought to determine its role in the dimorphic regulation of energy homeostasis. We tracked male and female WT and CAR deficient (CAR−/−) mice for over a year. During aging, CAR−/− male mice developed hypercortisism, obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis. Remarkably, the latter modifications were absent, or minor, in female CAR−/− mice. When ovariectomized, CAR−/− female mice developed identical patterns of metabolic disorders as observed in male mice. These results highlight the importance of steroid hormones in the regulation of energy metabolism by CAR. They unveil a sexually dimorphic role of CAR in the maintenance of endocrine and metabolic homeostasis underscoring the importance of considering sex in treatment of metabolic diseases.

scholarly journals Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

2006 ◽  
Vol 320 (1) ◽  
pp. 72-80 ◽  
Author(s):  
Stephanie R. Faucette ◽  
Tong-Cun Zhang ◽  
Rick Moore ◽  
Tatsuya Sueyoshi ◽  
Curtis J. Omiecinski ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Relative Activation
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