Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR
Open accessAbstract
The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans.
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Inverse agonists to suppress human CAR and agonists to activate human FXR are both pharmaceutically available.
“Inverse agonists to suppress human CAR and agonists for activation of human FXR are both pharmaceutically available (Hirschfield et al., 2015; Huang et al., 2004).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2004
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“Inverse agonists to suppress human CAR and agonists for activation of human FXR are both pharmaceutically available (Hirschfield et al., 2015; Huang et al., 2004).”
BackgroundSelf-citation
- Authors
- Huang, W., Zhang, J., Wei, P., Schrader, W. T., & Moore, D. D.
- Affiliations
- Baylor College of Medicine (US)
- X-Ceptor Therapeutics, Inc. (P.W.), San Diego, California 92121
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Moore, David D.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-10-01
- Volume
- 18
- Issue
- 10
- Pages
- 2402-2408
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2166406943
- Cited by
- 110
- References
- 33
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 8 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 3 · 2012: 6
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK62434)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK046546, U19 DK-62434, R01 DK46546, U19DK062434)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- meclizine, constitutive androstane receptor, inverse agonists, nuclear receptors, ligand-binding domain, SRC-1, phenobarbital, cytochrome P450 induction, Cyp2b10, CYP3A11, CYP1A2, xenobiotic metabolism
- MeSH terms
- Constitutive Androstane Receptor, Animals, Antiemetics, Cells, Cultured, Humans, Meclizine, Recombinant Proteins, RNA, Transcription Factors, Transfection, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Hepatocytes, Cell Line, Tumor, Mice
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