An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen
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 wi...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2001-04, Vol.98 (8), p.4611-4616 |
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| creator | Chan, Kaimin Han, Xiao-Dong Kan, Yuet Wai |
| description | 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 gcsHand gcsLas 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. |
| doi_str_mv | 10.1073/pnas.081082098 |
| format | Article |
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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 gcsHand gcsLas 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.081082098</identifier><identifier>PMID: 11287661</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acetaminophen - pharmacokinetics ; Alanine Transaminase - blood ; Analgesics ; Animals ; Base Sequence ; Biological Sciences ; Body weight ; DNA Primers ; DNA-Binding Proteins - physiology ; Dosage ; Enzymes ; Female ; Female animals ; Gene expression ; Gene Expression Profiling ; Genetics ; Genotypes ; Glutathione - blood ; Inactivation, Metabolic - physiology ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Male ; Male animals ; Mice ; NF-E2-Related Factor 2 ; Nrf2 protein ; Oxidation ; Oxidative Stress ; Survival Analysis ; Toxicology ; Trans-Activators - physiology ; Transcription factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2001-04, Vol.98 (8), p.4611-4616</ispartof><rights>Copyright 1993-2001 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Apr 10, 2001</rights><rights>Copyright © 2001, The National Academy of Sciences 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-e33647b7eef5d2a2bfce23915a6dcdb5b07533c740f9397c92ff455daffa5793</citedby><cites>FETCH-LOGICAL-c582t-e33647b7eef5d2a2bfce23915a6dcdb5b07533c740f9397c92ff455daffa5793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/98/8.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3055477$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3055477$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11287661$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, Kaimin</creatorcontrib><creatorcontrib>Han, Xiao-Dong</creatorcontrib><creatorcontrib>Kan, Yuet Wai</creatorcontrib><title>An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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 gcsHand gcsLas 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.</description><subject>Acetaminophen - pharmacokinetics</subject><subject>Alanine Transaminase - blood</subject><subject>Analgesics</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Biological Sciences</subject><subject>Body weight</subject><subject>DNA Primers</subject><subject>DNA-Binding Proteins - physiology</subject><subject>Dosage</subject><subject>Enzymes</subject><subject>Female</subject><subject>Female animals</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genetics</subject><subject>Genotypes</subject><subject>Glutathione - blood</subject><subject>Inactivation, Metabolic - physiology</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Male</subject><subject>Male animals</subject><subject>Mice</subject><subject>NF-E2-Related Factor 2</subject><subject>Nrf2 protein</subject><subject>Oxidation</subject><subject>Oxidative Stress</subject><subject>Survival Analysis</subject><subject>Toxicology</subject><subject>Trans-Activators - physiology</subject><subject>Transcription factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUFv1DAQhS0EokvhyglQxIFblrEdxw7istpSqFTRAz0iWY5jt14ldrCdavn3zWq3S0GcxtL73uiNH0KvMSwxcPpx9CotQWAQBBrxBC0wNLisqwaeogUA4aWoSHWCXqS0AYCGCXiOTjAmgtc1XqCfK19cDGOIWflcnE9eZxd8EWzxPVpSOF-sw9Cq7PxNcbV13fy6M8WPHE1Kn4ozk8PWWafVg2ulTVaD82G8Nf4lemZVn8yrwzxF1-dfrtffysurrxfr1WWpmSC5NJTWFW-5MZZ1RJHWakNog5mqO921rAXOKNW8AtvQhuuGWFsx1ilrFeMNPUWf92vHqR1Mp43PUfVyjG5Q8bcMysm_Fe9u5U24kxQLQWb7h4M9hl-TSVkOLmnT98qbMCWJ-fyFjPEZfP8PuAlT9PNlkgCugNdAZ2i5h3QMKUVjjzkwyF1lcleZPFY2G949Tv8HP3Q0A28PwM74IDdCClnVGD_K_19d2qnvs9nmGXyzBzcph3gkKTBWcU7vAdDltLg</recordid><startdate>20010410</startdate><enddate>20010410</enddate><creator>Chan, Kaimin</creator><creator>Han, Xiao-Dong</creator><creator>Kan, Yuet Wai</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7U7</scope><scope>5PM</scope></search><sort><creationdate>20010410</creationdate><title>An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen</title><author>Chan, Kaimin ; Han, Xiao-Dong ; Kan, Yuet Wai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c582t-e33647b7eef5d2a2bfce23915a6dcdb5b07533c740f9397c92ff455daffa5793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Acetaminophen - pharmacokinetics</topic><topic>Alanine Transaminase - blood</topic><topic>Analgesics</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Biological Sciences</topic><topic>Body weight</topic><topic>DNA Primers</topic><topic>DNA-Binding Proteins - physiology</topic><topic>Dosage</topic><topic>Enzymes</topic><topic>Female</topic><topic>Female animals</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genetics</topic><topic>Genotypes</topic><topic>Glutathione - blood</topic><topic>Inactivation, Metabolic - physiology</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Male</topic><topic>Male animals</topic><topic>Mice</topic><topic>NF-E2-Related Factor 2</topic><topic>Nrf2 protein</topic><topic>Oxidation</topic><topic>Oxidative Stress</topic><topic>Survival Analysis</topic><topic>Toxicology</topic><topic>Trans-Activators - physiology</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, Kaimin</creatorcontrib><creatorcontrib>Han, Xiao-Dong</creatorcontrib><creatorcontrib>Kan, Yuet Wai</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Toxicology Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chan, Kaimin</au><au>Han, Xiao-Dong</au><au>Kan, Yuet Wai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2001-04-10</date><risdate>2001</risdate><volume>98</volume><issue>8</issue><spage>4611</spage><epage>4616</epage><pages>4611-4616</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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 gcsHand gcsLas 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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>11287661</pmid><doi>10.1073/pnas.081082098</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetaminophen - pharmacokinetics Alanine Transaminase - blood Analgesics Animals Base Sequence Biological Sciences Body weight DNA Primers DNA-Binding Proteins - physiology Dosage Enzymes Female Female animals Gene expression Gene Expression Profiling Genetics Genotypes Glutathione - blood Inactivation, Metabolic - physiology Liver Liver - drug effects Liver - metabolism Liver - pathology Male Male animals Mice NF-E2-Related Factor 2 Nrf2 protein Oxidation Oxidative Stress Survival Analysis Toxicology Trans-Activators - physiology Transcription factors |
| title | An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen |
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