Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor
Open accessAbstract
The constitutive androstane receptor (CAR, NR1I3) is a central regulator of xenobiotic metabolism. CAR activation induces hepatic expression of detoxification enzymes and transporters and increases liver size. Here we show that CAR-mediated hepatomegaly is a transient, adaptive response to acute xenobiotic stress. In contrast, chronic CAR activation results in hepatocarcinogenesis. In both acute and chronic xenobiotic responses, hepatocyte DNA replication is increased and apoptosis is decreased. These effects are absent in CAR null mice, which are completely resistant to tumorigenic effects of chronic xenobiotic stress. In the acute response, direct up-regulation of Mdm2 expression by CAR contributes to both increased DNA replication and inhibition of p53-mediated apoptosis. These results demonstrate an essential role for CAR in regulating both liver homeostasis and tumorigenesis in response to xenobiotic stresses, and they also identify a specific molecular mechanism linking chronic environmental stress and tumor formation.
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Intrahepatic cholestasis can activate CAR.
“Intrahepatic cholestasis can also activate the constitutive androstane receptor (CAR, NR1I3) (Guo et al., 2003; Huang et al., 2005; Ma et al., 2009; Zhang et al., 2004)”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2005
CAR activation is the basis for phenobarbital-promoted non-genotoxic or mutagen-induced hepatocarcinogenesis in mice.
“CAR activation is the basis for phenobarbital promoted non-genotoxic or mutagen-induced hepatocarcinogenesis in mice (Huang et al., 2005; Yamamoto et al., 2004)”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2005
CAR promotes hepatocarcinogenesis independently of exogenous mutagens.
“which promotes hepatocarcinogenesis independent of exogenous mutagens (Huang et al., 2005; Yamamoto et al., 2004).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2005
CAR is a potent tumor promoter that drives non-genotoxic hepatocarcinogenesis.
“which is well known as a potent tumor promoter that drives non-genotoxic hepatocarcinogenesis (Guo et al., 2003; Huang et al., 2005; Yamamoto et al., 2004; Zhang et al., 2004).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2005
Elevated bile acids activate CAR.
“We and others have previously demonstrated that elevated bile acids, as observed in mice lacking circadian homeostasis, activates CAR (Guo et al., 2003; Huang et al., 2005; Ma et al., 2009; Zhang et al., 2004)”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Huang et al., 2005
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Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis
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“, 2004), which promotes hepatocarcinogenesis independent of exogenous mutagens (Huang et al., 2005; Yamamoto et al., 2004).”
BackgroundInfluentialSelf-citationNuclear receptors as therapeutic targets in cholestatic liver diseases
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- Authors
- Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G., & Moore, D. D.
- Affiliations
- Department of Molecular and Cellular Biology (W.H., J.Z., M.W., J.L., D.D.M.), Houston, Texas 77030
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Moore, David D.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-06-01
- Volume
- 19
- Issue
- 6
- Pages
- 1646-1653
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W1997933512
- Cited by
- 284
- References
- 42
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 12 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 19 · 2017: 17 · 2016: 15 · 2015: 22 · 2014: 21 · 2013: 17 · 2012: 15
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- School of Medicine, Stanford University
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK046546, DK062434, DK46546, R01 DK46546, U19DK062434)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- constitutive androstane receptor, xenobiotic stress, hepatomegaly, hepatocarcinogenesis, liver tumors, DNA replication, apoptosis, MDM2, p53, liver homeostasis, detoxification enzymes
- MeSH terms
- Constitutive Androstane Receptor, Animals, DNA, Flow Cytometry, HeLa Cells, Hepatomegaly, Humans, Liver, Liver Neoplasms, Mice, Transgenic, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, RNA, Time Factors, Transcription Factors, Transfection, Xenobiotics, Up-Regulation, Tumor Suppressor Protein p53, Apoptosis, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2, DNA Fragmentation
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