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

Haines, C. E.; Elcombe, Barbara M.; Chatham, Lynsey R.; Vardy, A. E.; Higgins, Larry G.; Elcombe, Clifford R.; Lake, Brian G.

doi:10.1016/j.tox.2018.02.001

Cited by 18 publications

(20 citation statements)

References 30 publications

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“…This issue makes comparisons of NR1I2 and NR1I3 activation between species difficult, although a limited number of selective ligands for rodent and hNR1I2 and hNR1I3 are available (Table 1) (Chan et al, 2011;Lemmen, Tozakidis, Bele, & Galla, 2013;. To help address this issue, humanised rodent models have been developed (Bauer et al, 2006;Haines et al, 2018).…”

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confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

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confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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“…Cyp2b induction and liver proliferation were for a long time considered as connected events in CAR activation, but recent studies have shown that a common hallmark of CAR activation is the induction of CYP2B6/Cyp2b10 enzymes. Liver proliferation, however, is restricted to rodent CAR [31,32]. The hCAR/hPXR/hCYP3A4 mice strain is, so far, one of the most realistic in vivo models of hCAR, responding to specific hCAR ligands and reflecting the hCAR specific transcriptional regulation limited to the mouse genome.…”

Section: Discussionmentioning

confidence: 99%

Diazepam Promotes Translocation of Human Constitutive Androstane Receptor (CAR) via Direct Interaction with the Ligand-Binding Domain

Skoda

Dušek

Drastík

et al. 2020

Cells

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The constitutive androstane receptor (CAR) is the essential regulator of genes involved both in xenobiotic and endobiotic metabolism. Diazepam has been shown as a potent stimulator of CAR nuclear translocation and is assumed as an indirect CAR activator not interacting with the CAR cavity. In this study, we sought to determine if diazepam is a ligand directly interacting with the CAR ligand binding domain (LBD) and if it regulates its target genes in a therapeutically relevant concentration. We used different CAR constructs in translocation and luciferase reporter assays, recombinant CAR-LBD in a TR-FRET assay, and target genes induction studied in primary human hepatocytes (PHHs), HepaRG cells, and in CAR humanized mice. We also used in silico docking and CAR-LBD mutants to characterize the interaction of diazepam and its metabolites with the CAR cavity. Diazepam and its metabolites such as nordazepam, temazepam, and oxazepam are activators of CAR+Ala in translocation and two-hybrid assays and fit the CAR cavity in docking experiments. In gene reporter assays with CAR3 and in the TR-FRET assay, only diazepam significantly interacts with CAR-LBD. Diazepam also promotes up-regulation of CYP2B6 in PHHs and in HepaRG cells. However, in humanized CAR mice, diazepam significantly induces neither CYP2B6 nor Cyp2b10 genes nor does it regulate critical genes involved in glucose and lipids metabolism and liver proliferation. Thus, we demonstrate that diazepam interacts with human CAR-LBD as a weak ligand, but it does not significantly affect expression of tested CAR target genes in CAR humanized mice.

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“…In addition, humans but not rodents have splicing isoforms that are differentially activated by ligands [ 89 ]. The robust hypertrophy of rodent liver to PB exposure seems to be missing in humans, perhaps due to differences in CAR target genes in these species [ 90 ].…”

Section: Key Characteristics Of Car and Its Activation Processmentioning

confidence: 99%

“…There is a lack of sufficiently selective tool compounds that are both non-toxic and have favorable pharmacokinetics for teasing out CAR-dependent functions in normal human hepatocytes [ 8 , 152 ]. The interpretation of animals studies are fraught with complications due to large species differences between CAR and PXR ligand profiles and their target genes—this may not be easily alleviated even by the use of humanized mice [ 90 ] without careful and wide-ranging analysis of affected target genes. Further development of long-term human hepatocyte cultures, in connection of modern gene knockdown techniques, is likely to provide better and disease-relevant models for utilization in studies of CAR and PXR [ 251 , 252 ].…”

Section: Future Directionsmentioning

confidence: 99%

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

Küblbeck

Niskanen

Honkakoski

2020

Cells

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During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.

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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

Cited by 18 publications

References 30 publications

The constitutive androstane receptor and pregnane X receptor in the brain

The constitutive androstane receptor and pregnane X receptor in the brain

Diazepam Promotes Translocation of Human Constitutive Androstane Receptor (CAR) via Direct Interaction with the Ligand-Binding Domain

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

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