PMID- 11134556
OWN - NLM
STAT- MEDLINE
DCOM- 20010222
LR  - 20220409
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 59
IP  - 1
DP  - 2001 Jan
TI  - High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated 
      with decreased expression of ARE-regulated drug metabolizing enzymes and 
      antioxidant genes.
PG  - 169-77
AB  - 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.
FAU - Enomoto, A
AU  - Enomoto A
AD  - Toxicology Division II, Laboratory of Pathology, Institute of Environmental 
      Toxicology, 4321 Uchimoriya, Mitsukaido, Ibaraki 303-0043, Japan. 
      enomoto@iinet.ne.jp
FAU - Itoh, K
AU  - Itoh K
FAU - Nagayoshi, E
AU  - Nagayoshi E
FAU - Haruta, J
AU  - Haruta J
FAU - Kimura, T
AU  - Kimura T
FAU - O'Connor, T
AU  - O'Connor T
FAU - Harada, T
AU  - Harada T
FAU - Yamamoto, M
AU  - Yamamoto M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 362O9ITL9D (Acetaminophen)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Acetaminophen/administration & dosage/pharmacokinetics/*toxicity
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - Chemical and Drug Induced Liver Injury/genetics/*metabolism/prevention & control
MH  - DNA-Binding Proteins/deficiency/genetics/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Fluorescent Antibody Technique, Indirect
MH  - *Gene Expression Regulation, Enzymologic
MH  - Glucuronosyltransferase/*genetics/metabolism
MH  - Glutamate-Cysteine Ligase/genetics/metabolism
MH  - Glutathione/analysis/*genetics/metabolism
MH  - Heterozygote
MH  - Homozygote
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mice, Knockout
MH  - Microsomes, Liver/drug effects/enzymology
MH  - NF-E2-Related Factor 2
MH  - RNA, Messenger/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Trans-Activators/deficiency/genetics/*metabolism
EDAT- 2001/01/03 11:00
MHDA- 2001/03/03 10:01
CRDT- 2001/01/03 11:00
PHST- 2001/01/03 11:00 [pubmed]
PHST- 2001/03/03 10:01 [medline]
PHST- 2001/01/03 11:00 [entrez]
AID - 10.1093/toxsci/59.1.169 [doi]
PST - ppublish
SO  - Toxicol Sci. 2001 Jan;59(1):169-77. doi: 10.1093/toxsci/59.1.169.