High Sensitivity of Nrf2 Knockout Mice to Acetaminophen Hepatotoxicity Associated with Decreased Expression of ARE-Regulated Drug Metabolizing Enzymes and Antioxidant Genes

Enomoto, A.

doi:10.1093/toxsci/59.1.169

Cited by 728Drug-Induced Hepatotoxicity and ProtectionGenomics, phytochemicals, and oxidative stressPharmacogenetics and Drug Metabolism

High Sensitivity of Nrf2 Knockout Mice to Acetaminophen Hepatotoxicity Associated with Decreased Expression of ARE-Regulated Drug Metabolizing Enzymes and Antioxidant Genes

Enomoto, A.·2001·Toxicological Sciences

DOI 10.1093/toxsci/59.1.169

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Abstract

Nrf2, which belongs to the basic leucine zipper (bZip) transcription factor family, has been implicated as a key molecule involved in antioxidant-responsive element (ARE)-mediated gene expression. In order to examine the role of Nrf2 in protection against xenobiotic toxicity, the sensitivity of nrf2 knockout mice to acetaminophen (N-acetyl-4-aminophenol (APAP)) was analyzed. The saturation of detoxification pathways after high levels of exposure to APAP is known to induce hepatotoxicity. Two factors important in its detoxification are UDP-glucuronosyltransferase (UDP-GT), an ARE-regulated phase-II drug-metabolizing enzyme, and glutathione (GSH), an antioxidant molecule whose synthesis depends on ARE-regulated gamma-glutamylcysteine synthetase (gammaGCS). Two- to 4-month-old male mice were orally administered a single dose of APAP at 0, 150, 300, or 600 mg/kg. Doses of 300 mg/kg APAP or greater caused death in the homozygous knockout mice only, and those that survived showed a greater severity in hepatic damage than the wild-type mice, as demonstrated by increased plasma alanine aminotransferase activity, decreased hepatic non-protein sulfhydryl (NPSH) content, and centrilobular hepatocellular necrosis. The high sensitivity of Nrf2-deficient mice was confirmed from observations made at 0, 2, 8, and 24 h after dosing with 300 mg/kg APAP; increased anti-APAP immunoreactivity was also noted in their livers at 2 h. Untreated homozygous knockout mice showed both a lower UDP-GT activity and NPSH content, which corresponded to decreased mRNA levels of UDP-GT (Ugt1a6) and the heavy chain of gammaGCS, respectively. These results show that Nrf2 plays a protective role against APAP hepatotoxicity by regulating both drug metabolizing enzymes and antioxidant genes through the ARE.

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Nrf2 KO mice and Trsp KO mice are not anemic; but hemolytic anemia can be induced by treatment with oxidant drugs.
“Nrf2 KO mice and Trsp KO mice are not anemic; but hemolytic anemia can be induced by treatment with oxidant drugs (54).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [54]

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Authors: Enomoto, A.
Affiliations: The Institute of Environmental Toxicology (JP)
Corresponding author: Enomoto, A.
Venue: Toxicological Sciences
Publisher: Oxford University Press (OUP)
Published: 2001-01-01
Volume: 59
Issue: 1
Pages: 169-177
ISSN: 1096-0929 (ISSN-L)
DOI: 10.1093/toxsci/59.1.169
OpenAlex: W2003867270
Cited by: 728
References: 42
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FWCI: 22.39
Type: journal article
Language: en
Open access: closed
Locations: Toxicological Sciences (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: Nrf2, acetaminophen hepatotoxicity, antioxidant response element, UDP-glucuronosyltransferase, gamma-glutamylcysteine synthetase, glutathione, drug-metabolizing enzymes, antioxidant genes, xenobiotic detoxification, liver necrosis, non-protein sulfhydryl groups, Nrf2 knockout mice, phase II metabolism
MeSH terms: Acetaminophen, Alanine Transaminase, Animals, DNA-Binding Proteins, Dose-Response Relationship, Drug, Glutamate-Cysteine Ligase, Glutathione, Heterozygote, Homozygote, Male, Mice, Inbred ICR, Microsomes, Liver, RNA, Messenger, Glucuronosyltransferase, Trans-Activators, Gene Expression Regulation, Enzymologic, Mice, Knockout, Fluorescent Antibody Technique, Indirect, Reverse Transcriptase Polymerase Chain Reaction, NF-E2-Related Factor 2, Mice, Chemical and Drug Induced Liver Injury

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High Sensitivity of Nrf2 Knockout Mice to Acetaminophen Hepatotoxicity Associated with Decreased Expression of ARE-Regulated Drug Metabolizing Enzymes and Antioxidant Genes

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