Home LiteratureArticle Details
PMID: 11287661 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 8 ·2001-04-10 ·Pages 4611-6

Chan K, Han XD, Kan YW

Abstract

Nrf2, a member of the "cap 'n collar" group of transcription factors, is important for protecting cells against oxidative damage. We investigated its role in the detoxification of acetaminophen [N-acetyl-p-aminophenol (APAP)]-induced hepatotoxicity. When Nrf2 knockout (Nrf2(-/-)) and wild-type mice were given APAP by i.p. injection, the Nrf2(-/-) mice were highly susceptible to APAP treatment. With doses of APAP that were tolerated by wild-type mice, the Nrf2(-/-) mice died of liver failure. When hepatic glutathione was depleted after a dose of 400 mg/kg of APAP, the wild-type mice were able to compensate and regain the normal glutathione level. In contrast, the glutathione level in the Nrf2(-/-) mice was not compensated and remained low. This was because of the decrease in the gene expression of gcs(H) and gcs(L) as well as gss in the livers of the Nrf2(-/-) mice. In addition, the expression of ugt1a6 and gstpi that detoxify APAP by conjugation was also decreased. This increased susceptibility of the Nrf2(-/-) mice to APAP, because of an impaired capacity to replenish their glutathione stores, compounded with a decreased detoxification capability, highlights the importance of Nrf2 in the regulation of glutathione synthesis and cellular detoxification processes.

MeSH Terms
Acetaminophen/pharmacokinetics Alanine Transaminase/blood Animals Base Sequence DNA Primers DNA-Binding Proteins/physiology Female Gene Expression Profiling Glutathione/blood Inactivation, Metabolic/physiology Liver/drug effects,metabolism,pathology Male Mice NF-E2-Related Factor 2 Oxidative Stress Survival Analysis Trans-Activators/physiology
Chemicals
DNA Primers DNA-Binding Proteins NF-E2-Related Factor 2 Nfe2l2 protein, mouse Trans-Activators Acetaminophen Alanine Transaminase Glutathione
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Chan K
Cardiovascular Research Institute, Department of Laboratory Medicine and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0793, USA.
Han X D
Kan Y W
References (25)
25 references, click to expand
  1. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene.
    J Biol Chem. 1999 Sep 10;274(37):26071-8 PMID: 10473555
  2. Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element.
    Biochem Biophys Res Commun. 1999 Aug 11;261(3):661-8 PMID: 10441483
  3. Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2.
    J Biol Chem. 1999 Nov 19;274(47):33627-36 PMID: 10559251
  4. The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in response to oxidative stress-inducing agents. Role for Nrf1 in gamma-gcs(l) and gss expression in mouse fibroblasts.
    J Biol Chem. 1999 Dec 24;274(52):37491-8 PMID: 10601325
  5. Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein.
    Biochim Biophys Acta. 2000 Dec 15;1517(1):19-26 PMID: 11118612
  6. The "beta-like-globin" gene domain in human erythroid cells.
    Proc Natl Acad Sci U S A. 1985 Oct;82(19):6384-8 PMID: 3879975
  7. A developmentally stable chromatin structure in the human beta-globin gene cluster.
    Proc Natl Acad Sci U S A. 1986 Mar;83(5):1359-63 PMID: 3456593
  8. Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin-expressing hybrids.
    Nucleic Acids Res. 1987 Dec 23;15(24):10159-77 PMID: 3480506
  9. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity.
    J Biol Chem. 1991 Jun 25;266(18):11632-9 PMID: 1646813
  10. Chemical and molecular regulation of enzymes that detoxify carcinogens.
    Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2965-9 PMID: 8385353
  11. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein.
    Nature. 1993 Apr 22;362(6422):722-8 PMID: 8469283
  12. Isolation of cDNA encoding the human NF-E2 protein.
    Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11366-70 PMID: 8248255
  13. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast.
    Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11371-5 PMID: 8248256
  14. Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression.
    Nucleic Acids Res. 1994 Jun 25;22(12):2383-91 PMID: 8036168
  15. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.
    Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926-30 PMID: 7937919
  16. ARE- and TRE-mediated regulation of gene expression. Response to xenobiotics and antioxidants.
    J Biol Chem. 1995 Mar 24;270(12):6894-900 PMID: 7896838
  17. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site.
    Mol Cell Biol. 1996 Nov;16(11):6083-95 PMID: 8887638
  18. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene.
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14960-5 PMID: 8962164
  19. Functional antioxidant responsive elements.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5361-6 PMID: 9144242
  20. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.
    Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22 PMID: 9240432
  21. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes.
    Oncogene. 1998 Dec 17;17(24):3145-56 PMID: 9872330
  22. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.
    Genes Dev. 1999 Jan 1;13(1):76-86 PMID: 9887101
  23. Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3.
    J Biol Chem. 1999 Mar 5;274(10):6443-52 PMID: 10037736
  24. Regulation of hepatic glutathione synthesis: current concepts and controversies.
    FASEB J. 1999 Jul;13(10):1169-83 PMID: 10385608
  25. Nrf2 is essential for protection against acute pulmonary injury in mice.
    Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12731-6 PMID: 10535991
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.081082098
Published
2001-04-10
Epub
2001-00-03
Pages
4611-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC31882
Subset
IM
Grants
NIDDK NIH HHS · R37 DK016666 · United States
NIDDK NIH HHS · DK16666 · United States
NIDDK NIH HHS · T32 DK007636 · United States
NIDDK NIH HHS · DK50267 · United States
NIDDK NIH HHS · DK07636 · United States
NIDDK NIH HHS · R01 DK016666 · United States
External Links
PubMed source DOI: 10.1073/pnas.081082098 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2