T0901317, a potent LXR agonist, is an inverse agonist of CAR

Kanno, Yuichiro; Tanuma, Nobuaki; Takahashi, Ami; Inouye, Yoshio

doi:10.2131/jts.38.309

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…More recently, the potent LXR and hPXR agonist TO901317 was described as being an inverse agonist of the human, mouse, and rat orthologs of CAR, with an estimated IC 50 of 2.2 μM [35]. The potent agonist CITCO reverses the inhibitory effect of TO901317 implying a competitive inhibition modality.…”

Section: Car Inhibitorsmentioning

confidence: 99%

Small-molecule modulators of the constitutive androstane receptor

Cherian

Chai

Chen

2015

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The constitutive androstane receptor (CAR) induces drug-metabolizing enzymes for xenobiotic metabolism. Areas covered This review covers recent advances in elucidating the biological functions of CAR and its modulation by a growing number of agonists and inhibitors. Expert opinion Extrapolation of animal CAR function to that of humans should be carefully scrutinized, particularly when rodents are used in evaluating the metabolic profile and carcinogenic properties of clinical drugs and environmental chemicals. Continuous efforts are needed to discover novel CAR inhibitors, with extensive understanding of their inhibitory mechanism, species selectivity, and discriminating power against other xenobiotic sensors.

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Section: Car Inhibitorsmentioning

confidence: 99%

Small-molecule modulators of the constitutive androstane receptor

Cherian

Chai

Chen

2015

Expert Opinion on Drug Metabolism & Toxicology

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“…For example, clotrimazole, T0901317, and PK11195 are not only agonists of hPXR but also inverse agonists of hCAR (Moore et al, 2000;Li et al, 2008;Kanno et al, 2013). In the current study, the basal transcriptional activity of ligand-free hCAR was not affected by NigC at concentrations of up to 10 mM, although a little but significant suppression was observed at 25 mM (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

Kanno¹,

Yatsu²,

Li³

et al. 2014

Drug Metab Dispos

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Pregnane X receptor (PXR) is known as a xenosensor, playing a key role in response to xenochemical stimuli. Activation of PXR enhanced expression of various drug-metabolizing enzymes and transporters such as cytochrome P450 3A4 (CYP3A4). During a screening of a natural compounds library for novel ligands of human xenosensing receptors by the mammalian one-hybrid assay, two cyclohexene-type amide alkaloids were isolated, with nigramide C (NigC) showing the most potent activation of human PXR (hPXR). NigC-mediated hPXR activation was enhanced by overexpression of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor g, coactivator 1a, and protein arginine methyltransferase 1. A direct interaction between the ligand-binding domain of hPXR and the receptor interaction domain of SRC1 was observed. NigC induced the expression of endogenous CYP3A4 mRNA and protein in both cultured hepatoma cells and primary hepatocytes. However, in primary hepatocytes, the relative agonist activity of NigC was not as potent as that of rifampicin, probably because of lower metabolic stability of NigC in these cells. In conclusion, NigC was found to be an effective agonist of hPXR. NigC is a useful tool for investigation of hPXR function.

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“…Segments of the receptor interaction domains of SRC‐1 (SRC‐1/RID, 569–781) and the nuclear receptor corepressor NCoR1 (NCoR1/RID, 1574–2338) were cloned into pcDNA5‐GAL4/DBD (Kanno et al. ). The preparation of the PBREM‐driven luciferase reporter plasmid (PBREM‐Luc) has been described elsewhere (Kanno et al.…”

Section: Methodsmentioning

confidence: 99%

Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor

Kanno

Tanuma

Yatsu

et al. 2014

Pharmacology Res & Perspec

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The constitutive androstane receptor (CAR, NR1I3) is very important for drug development and for understanding pharmacokinetic drug–drug interactions. We screened by mammalian one hybrid assay among natural compounds to discover novel ligands of human constitutive androstane receptor (hCAR). hCAR transcriptional activity was measured by luciferase assay and mRNA levels of CYP2B6 and CYP3A4 in HepTR-hCAR cells and human primary hepatocytes were measured by real-time RT-PCR. Nigramide J (NJ) whose efficacy is comparable to those of hitherto known inverse agonists such as clotrimazole, PK11195, and ethinylestradiol. NJ is a naturally occurring cyclohexane-type amide alkaloid that was isolated from the roots of Piper nigrum. The suppressive effect of NJ on the CAR-dependent transcriptional activity was found to be species specific, in the descending order of hCAR, rat CAR, and mouse CAR. The unliganded hCAR-dependent transactivation of reporter and endogenous genes was suppressed by NJ at concentrations higher than 5 μmol/L. The ligand-binding cavity of hCAR was shared by NJ and CITCO, because they were competitive in the binding to hCAR. NJ interfered with the interaction of hCAR with coactivator SRC-1, but not with its interaction with the corepressor NCoR1. Furthermore, NJ is agonist of human pregnane X receptor (hPXR). NJ is a dual ligand of hCAR and hPXR, being an agonist of hPXR and an inverse agonist of hCAR.

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T0901317, a potent LXR agonist, is an inverse agonist of CAR

Cited by 17 publications

References 28 publications

Small-molecule modulators of the constitutive androstane receptor

Small-molecule modulators of the constitutive androstane receptor

Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor

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