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

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.

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

Digestive and Liver Disease ◽

10.1016/j.dld.2018.10.008 ◽

2019 ◽

Vol 51 (2) ◽

pp. 226-235 ◽

Cited By ~ 2

Author(s):

Daisuke Uehara ◽

Hiroki Tojima ◽

Satoru Kakizaki ◽

Yuichi Yamazaki ◽

Norio Horiguchi ◽

...

Keyword(s):

Constitutive Androstane Receptor ◽

Pregnane X Receptor

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Transactivation Assays that Identify Indirect and Direct Activators of Human Pregnane X Receptor (PXR, NR1I2) and Constitutive Androstane Receptor (CAR, NR1I3)

Drug Metabolism Letters ◽

10.2174/1872312812666171207113639 ◽

2018 ◽

Vol 11 (2) ◽

Cited By ~ 1

Author(s):

Marija Pinne ◽

Elsa Ponce ◽

Judy L. Raucy

Keyword(s):

Constitutive Androstane Receptor ◽

Pregnane X Receptor

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Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism

Archives of Toxicology ◽

10.1007/s00204-020-02916-x ◽

2020 ◽

Author(s):

Tomas Smutny ◽

Lucie Hyrsova ◽

Albert Braeuning ◽

Magnus Ingelman-Sundberg ◽

Petr Pavek

Keyword(s):

Transcriptional Regulation ◽

Drug Metabolism ◽

Interindividual Variability ◽

Pregnane X Receptor ◽

Post Transcriptional Regulation

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

International Journal of Molecular Sciences ◽

10.3390/ijms20092331 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2331 ◽

Cited By ~ 3

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.

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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

Toxicological Sciences ◽

10.1093/toxsci/kfaa125 ◽

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.

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