Importance of Hepatic Induction of Constitutive Androstane Receptor and Other Transcription Factors That Regulate Xenobiotic Metabolism and Transport
Abstract
Aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-alpha (PPARalpha), and nuclear factor-E2-related factor 2 (Nrf2) are transcription factors that mediate xenobiotic induction of biotransformation enzymes and transporters. The purpose of this study was to determine the tissue distribution and xenobiotic induction of these transcription factors and their associated target genes in mice. Many of these transcription factors were most highly expressed in extrahepatic tissues. CAR expression in female liver was twice that in male liver. This corresponded with greater induction of the CAR target genes Cyp2b10 and multidrug resistance-associated protein (Mrp) 4 by the CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in female liver than in male liver. Mice were treated with xenobiotic activators of AhR, CAR, PXR, PPARalpha, or Nrf2 and their associated marker genes were highly induced in liver by these xenobiotic activators. Transcription factor target gene induction occurred with minimal induction of their associated transcription factors. CAR expression was induced by the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), leading to increased basal expression of Cyp2b10 mRNA and enhanced induction of Cyp2b10 by TCPOBOP. Mrp2, 3, and 4 induction was augmented by cotreatment with TCDD and TCPOBOP compared with treatment with either compound alone. These studies illustra…
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Female livers are more sensitive to CAR activation.
“and the fact that female livers are more sensitive to CAR activation,65”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [65]
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- Authors
- Petrick, J. S., & Klaassen, C. D.
- Affiliations
- University of Kansas Medical Center (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 35
- Issue
- 10
- Pages
- 1806-1815
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2154871647
- Cited by
- 85
- References
- 42
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 2 · 2014: 6 · 2013: 2 · 2012: 7
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (ES 09716, ES 09649, ES-07079, R01ES009649, T32ES007079, R01ES009716)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- constitutive androstane receptor, aryl hydrocarbon receptor, pregnane X receptor, PPARα, Nrf2, xenobiotic induction, hepatic gene expression, Cyp2b10, multidrug resistance-associated protein, MRP2, MRP3, MRP4, TCPOBOP, TCDD, transcriptional regulation
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Cytochrome P-450 Enzyme System, Enzyme Induction, Female, Liver, Male, Mice, Inbred C57BL, Pregnancy, Pyridines, RNA, Messenger, Tissue Distribution, Transcription Factors, Xenobiotics, Gene Expression, ATP Binding Cassette Transporter, Subfamily B, Mice
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