Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jul;11(7):1099-114.
doi: 10.1517/17425255.2015.1043887. Epub 2015 May 15.

Small-molecule modulators of the constitutive androstane receptor

Milu T Cherian  1 , Sergio C Chai, Taosheng Chen
Affiliations
Review

Small-molecule modulators of the constitutive androstane receptor

Milu T Cherian et al. Expert Opin Drug Metab Toxicol. 2015 Jul.

Abstract

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.

Keywords: constitutive androstane receptor; drug–drug interactions; small-molecule; xenobiotic metabolism.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CAR inhibitors as reported for human (H), mouse (M) and rat (R) CAR.
Figure 2
Figure 2
Crystal structures of the CAR LBD (cartoon representation) in complex with a ligand (stick representation) A) hCAR with CITCO (pdb 1XVP); B) mCAR with androstenol (pdb 1XNX); C) hCAR with 5β-pregnanedione (pdb 1XV9); D) mCAR with TCPOBOP (pdb 1XLS). Oxygen, nitrogen, and chlorine atoms are depicted in red, blue, and dark green, respectively. The residues Phe161, Asn165, Phe234, and Tyr326 (Figure 2A, carbon atoms in orange) form the barrier that obstructs ligand access to the AF-2 helix and helix-x residues Leu336, Met340, Leu343 and Cys347 (carbon atoms in purple). All structures are depicted in the same orientation for comparison.
See this image and copyright information in PMC

References

    1. Baes M, Gulick T, Choi HS, et al. A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol. 1994;14:1544–52. - PMC - PubMed
    1. Wang H, Faucette S, Sueyoshi T, et al. A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem. 2003;278:14146–52. - PubMed
    1. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–9. - PMC - PubMed
    1. Min G, Kim H, Bae Y, et al. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J Biol Chem. 2002;277:34626–33. - PubMed
    1. Choi HS, Chung M, Tzameli I, et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem. 1997;272:23565–71. - PubMed

Publication types

MeSH terms

Substances