Comparison of the hepatic and thyroid gland effects of sodium phenobarbital in wild type and constitutive androstane receptor (CAR) knockout rats and pregnenolone-16α-carbonitrile in wild type and pregnane X receptor (PXR) knockout rats

Toxicology ◽  
2018 ◽  
Vol 400-401 ◽  
pp. 20-27 ◽  
Author(s):  
Corinne Haines ◽  
Lynsey R. Chatham ◽  
Audrey Vardy ◽  
Clifford R. Elcombe ◽  
John R. Foster ◽  
...  
Keyword(s):  
Thyroid Gland ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Wild Type ◽  
Sodium Phenobarbital

Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes

Toxicology ◽  
2018 ◽  
Vol 396-397 ◽  
pp. 23-32 ◽  
Author(s):  
Corinne Haines ◽  
Barbara M. Elcombe ◽  
Lynsey R. Chatham ◽  
Audrey Vardy ◽  
Larry G. Higgins ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Human Hepatocytes ◽  
Wild Type ◽  
Sodium Phenobarbital

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 Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

2012 ◽  
Vol 57 (3) ◽  
pp. 1332-1338 ◽  
Author(s):  
Masato Ohbuchi ◽  
Kouichi Yoshinari ◽  
Hayato Kaneko ◽  
Satoru Matsumoto ◽  
Akiko Inoue ◽  
...  
Keyword(s):  
Target Genes ◽  
Mammalian Species ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Human Hepatocytes ◽  
Mrna Levels ◽  
Wild Type ◽  
Primary Human Hepatocytes ◽  
Metabolic Activities ◽  
Species Specific

ABSTRACTThe antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type,Pxr-null,Car-null, andPxr- andCar-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed inPxr-null andCar-null mice but not inPxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. HepaticCyp3a11mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels ofCYP3A4andCYP2B6(human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR- and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

scholarly journals Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Ines L. Paraiso ◽  
Thai Q. Tran ◽  
Armando Alcazar Magana ◽  
Payel Kundu ◽  
Jaewoo Choi ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Liver Dysfunction ◽  
High Fat Diet ◽  
Critical Role ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Gene Profiling ◽  
Wild Type ◽  
Dependent Relationship

The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXRLiver−/−) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis and decreased BA concentrations in FXRLiver−/− mice, the effect being stronger in male mice. XN induced the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) gene expression in the liver of FXRLiver−/− mice. These findings suggest that activation of BA detoxification pathways represents the predominant mechanism for controlling hydrophobic BA concentrations in FXRLiver−/− mice. Collectively, these data indicated sex-dependent relationship between FXR, lipids and BAs, and suggest that XN ameliorates HFD-induced liver dysfunction via FXR-dependent and independent signaling.

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

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
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