Small-molecule modulators of the constitutive androstane receptor

Cherian, Milu T.; Chai, Sergio C.; Chen, Taosheng

doi:10.1517/17425255.2015.1043887

Cited by 32 publications

(24 citation statements)

References 161 publications

(151 reference statements)

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“…The small but flexible LBD of CAR allows it to bind and respond to xenobiotics with a variety of chemical structures (Cherian et al, 2015a). …”

Section: Discussionmentioning

confidence: 99%

“…CINPA1 [ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate] is a potent inhibitor of human constitutive androstane receptor (hCAR) that was recently discovered by using a directed chemical screening approach; unlike other reported inhibitors of CAR, CINPA1 does not activate PXR (Cherian et al, 2015b). Although the most studied hCAR isoform, hCAR1, is constitutively active when exogenously expressed in cultured cells, it can still be modulated by both activators and inhibitors (Honkakoski et al, 2003;Cherian et al, 2015a). CAR transcriptionally regulates the expression of CYP2B6 and CYP3A4 by binding to the xenobiotic response elements in the promoter regions of these genes (Sueyoshi et al, 1999;Goodwin et al, 2002;Li et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

Cherian

Yang

Chai

et al. 2016

Drug Metabolism and Disposition

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The constitutive androstane receptor (CAR) regulates the expression of genes involved in drug metabolism and other processes. A specific inhibitor of CAR is critical for modulating constitutive CAR activity. We recently described a specific small-molecule inhibitor of CAR, CINPA1 (ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate), which is capable of reducing CAR-mediated transcription by changing the coregulator recruitment pattern and reducing CAR occupancy at the promoter regions of its target genes. In this study, we showed that CINPA1 is converted to two main metabolites in human liver microsomes. By using cell-based reporter gene and biochemical coregulator recruitment assays, we showed that although metabolite 1 was very weak in inhibiting CAR function and disrupting CAR-coactivator interaction, metabolite 2 was inactive in this regard. Docking studies using the CAR ligand-binding domain structure showed that although CINPA1 and metabolite 1 can bind in the CAR ligand-binding pocket, metabolite 2 may be incapable of the molecular interactions required for binding. These results indicate that the metabolites of CINPA1 may not interfere with the action of CINPA1. We also used in vitro enzyme assays to identify the cytochrome P450 enzymes responsible for metabolizing CINPA1 in human liver microsomes and showed that CINPA1 was first converted to metabolite 1 by CYP3A4 and then further metabolized by CYP2D6 to metabolite 2. Identification and characterization of the metabolites of CINPA1 enabled structureactivity relationship studies of this family of small molecules and provided information to guide in vivo pharmacological studies.

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“…The small but flexible LBD of CAR allows it to bind and respond to xenobiotics with a variety of chemical structures (Cherian et al, 2015a). …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

Cherian

Yang

Chai

et al. 2016

Drug Metabolism and Disposition

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“…Since CAR has a large hydrophobic LBD pocket, a variety of chemical xenobiotics can activate it, such as clinical drugs, insecticides, flavonoids, terpenoids, polyphenols, environmental chemicals, and others [ 66 , 67 ]. Interestingly, CAR exhibits arresting species specificity in the ligand binding recognition between human and rodent, though both species use the same DNA response element sequences to recruit CAR.…”

Section: The Initial Characterization Of Ppar Car and Lxrmentioning

confidence: 99%

The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis

Zhai

Wang

2018

IJMS

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The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis.

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“…The expression of CYP450 enzymes is induced by nuclear receptors that respond to xenobiotics. Many CYP450 enzymes are transcriptionally regulated by the xenobiotic receptors pregnane X receptor (PXR, also known as NR1I2, SXR, or PAR) and constitutive androstane receptor (CAR; NR1I3) [ 6 , 7 , 8 , 9 ]. We will discuss the involvement of PXR and CAR in herbal supplement hepatotoxicity later in this review.…”

Section: Introductionmentioning

confidence: 99%

Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

Brewer

Chen

2017

IJMS

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Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s.

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Small-molecule modulators of the constitutive androstane receptor

Cited by 32 publications

References 161 publications

Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis

Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

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