Cited by 85Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

Importance of Hepatic Induction of Constitutive Androstane Receptor and Other Transcription Factors That Regulate Xenobiotic Metabolism and Transport

Petrick, Jay S., Klaassen, Curtis D.·2007·Drug Metabolism and Disposition

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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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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