Open AccessNigramide J is a novel potent inverse agonist of the human constitutive androstane receptor
Author(s) -
Kanno Yuichiro,
Tanuma Nobuaki,
Yatsu Tomofumi,
Li Wei,
Koike Kazuo,
Inouye Yoshio
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.18
Subject(s) - constitutive androstane receptor , transactivation , inverse agonist , agonist , pharmacology , allosteric modulator , chemistry , reporter gene , pregnane x receptor , receptor , androstane , nuclear receptor , biology , biochemistry , gene expression , stereochemistry , gene , transcription factor
The constitutive androstane receptor ( CAR , NR 1I3) 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 μ mol/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 .