Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose
Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the...
Gespeichert in:
| Veröffentlicht in: | PloS one 2020-04, Vol.15 (4), p.e0231173-e0231173 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e0231173 |
|---|---|
| container_issue | 4 |
| container_start_page | e0231173 |
| container_title | PloS one |
| container_volume | 15 |
| creator | Piel, Sarah Chamkha, Imen Dehlin, Adam Kozak Ehinger, Johannes K Sjövall, Fredrik Elmér, Eskil Hansson, Magnus J |
| description | Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury. |
| doi_str_mv | 10.1371/journal.pone.0231173 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2386851265</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A619584397</galeid><doaj_id>oai_doaj_org_article_38c8ab6c0c2b4962a46ddb921cd97c16</doaj_id><sourcerecordid>A619584397</sourcerecordid><originalsourceid>FETCH-LOGICAL-c761t-ff4f06f400dbf26ed4438da8fd15959ceba5ab48131931aa755b74bca5d8a5933</originalsourceid><addsrcrecordid>eNqNk12L1DAUhoso7rr6D0QLgujFjE3z0fZGWAY_FhYW_LoNp8npTJa0qUmz6r833ZldtrIXUkJD-pyn7ZucLHtOijWhFXl36aIfwK5HN-C6KCkhFX2QHZOGlitRFvThnflR9iSEy6LgtBbicXZEy5ITVlfHWdygtasRfY_QWsxDVMoMMGE-eqd93IbcY1AR895MTu3coL0BOy-OxsNk3JCbIVfJEi34vHcabchdl4OKyQIKJ-jN4MYdDrm7Qq9dwKfZow5swGeH-0n2_eOHb5vPq_OLT2eb0_OVqgSZVl3HukJ0rCh025UCNWO01lB3mvCGNwpb4NCymtD0pwSg4rytWKuA6xp4Q-lJ9nLvHa0L8pBYkGWKoeakFDwRZ3tCO7iUozc9-D_SgZHXC85vJfjJKIuS1qqGVqhClS1rRAlMaN02JVG6qRQRyXW-d4VfOMZ2YbNxTKNNQwaUUFElCs4lY7WSDLGRLRVc6kojJ6iF5ph07w8fH9setcJh8mAX1uWTwezk1l3JilBe1kUSvDkIvPsZMUyyN2HeKRjQxesYqlIUjM4xvPoHvT-sA7WFlIcZOpfeq2apPBWk4TWjTZWo9T1UujT2RqXT2pm0vih4uyhIzIS_py3EEOTZ1y__z178WLKv77A7BDvtgrNxPrRhCbI9qLwLwWN3GzIp5NxsN2nIudnkodlS2Yu7G3RbdNNd9C-voSdu</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2386851265</pqid></control><display><type>article</type><title>Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose</title><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SWEPUB Freely available online</source><source>Free Full-Text Journals in Chemistry</source><source>Public Library of Science (PLoS)</source><creator>Piel, Sarah ; Chamkha, Imen ; Dehlin, Adam Kozak ; Ehinger, Johannes K ; Sjövall, Fredrik ; Elmér, Eskil ; Hansson, Magnus J</creator><creatorcontrib>Piel, Sarah ; Chamkha, Imen ; Dehlin, Adam Kozak ; Ehinger, Johannes K ; Sjövall, Fredrik ; Elmér, Eskil ; Hansson, Magnus J</creatorcontrib><description>Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0231173</identifier><identifier>PMID: 32251487</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetaminophen ; Acetylcysteine ; Analgesics ; Analysis ; Antioxidants ; Antioxidants (Nutrients) ; Automation ; Basic Medicine ; Biology and Life Sciences ; Blood platelets ; Care and treatment ; Cells (Biology) ; Characterization ; Chemical compounds ; Drug dosages ; Drug therapy ; Drugs ; EDTA ; Electron transport chain ; Farmakologi och toxikologi ; Health aspects ; Hepatocytes ; Injuries ; Liver ; Liver diseases ; Liver failure ; Medical and Health Sciences ; Medical research ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Medicinska och farmaceutiska grundvetenskaper ; Mitochondria ; NADH ; Nicotinamide adenine dinucleotide ; Nonprescription drugs ; Novels ; Overdose ; Oxidative stress ; Pain ; Permeability ; Pharmaceuticals ; Pharmacology and Toxicology ; Phosphorylation ; Prodrugs ; Respiration ; Therapeutic applications ; Toxicity</subject><ispartof>PloS one, 2020-04, Vol.15 (4), p.e0231173-e0231173</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Piel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Piel et al 2020 Piel et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c761t-ff4f06f400dbf26ed4438da8fd15959ceba5ab48131931aa755b74bca5d8a5933</citedby><cites>FETCH-LOGICAL-c761t-ff4f06f400dbf26ed4438da8fd15959ceba5ab48131931aa755b74bca5d8a5933</cites><orcidid>0000-0002-2417-5767 ; 0000-0001-5612-0325 ; 0000-0002-1779-3532</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135280/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135280/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32251487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/a73c6055-448c-4ee9-b365-d7de51ed6d5e$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Piel, Sarah</creatorcontrib><creatorcontrib>Chamkha, Imen</creatorcontrib><creatorcontrib>Dehlin, Adam Kozak</creatorcontrib><creatorcontrib>Ehinger, Johannes K</creatorcontrib><creatorcontrib>Sjövall, Fredrik</creatorcontrib><creatorcontrib>Elmér, Eskil</creatorcontrib><creatorcontrib>Hansson, Magnus J</creatorcontrib><title>Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.</description><subject>Acetaminophen</subject><subject>Acetylcysteine</subject><subject>Analgesics</subject><subject>Analysis</subject><subject>Antioxidants</subject><subject>Antioxidants (Nutrients)</subject><subject>Automation</subject><subject>Basic Medicine</subject><subject>Biology and Life Sciences</subject><subject>Blood platelets</subject><subject>Care and treatment</subject><subject>Cells (Biology)</subject><subject>Characterization</subject><subject>Chemical compounds</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>EDTA</subject><subject>Electron transport chain</subject><subject>Farmakologi och toxikologi</subject><subject>Health aspects</subject><subject>Hepatocytes</subject><subject>Injuries</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Liver failure</subject><subject>Medical and Health Sciences</subject><subject>Medical research</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>Mitochondria</subject><subject>NADH</subject><subject>Nicotinamide adenine dinucleotide</subject><subject>Nonprescription drugs</subject><subject>Novels</subject><subject>Overdose</subject><subject>Oxidative stress</subject><subject>Pain</subject><subject>Permeability</subject><subject>Pharmaceuticals</subject><subject>Pharmacology and Toxicology</subject><subject>Phosphorylation</subject><subject>Prodrugs</subject><subject>Respiration</subject><subject>Therapeutic applications</subject><subject>Toxicity</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QLgujFjE3z0fZGWAY_FhYW_LoNp8npTJa0qUmz6r833ZldtrIXUkJD-pyn7ZucLHtOijWhFXl36aIfwK5HN-C6KCkhFX2QHZOGlitRFvThnflR9iSEy6LgtBbicXZEy5ITVlfHWdygtasRfY_QWsxDVMoMMGE-eqd93IbcY1AR895MTu3coL0BOy-OxsNk3JCbIVfJEi34vHcabchdl4OKyQIKJ-jN4MYdDrm7Qq9dwKfZow5swGeH-0n2_eOHb5vPq_OLT2eb0_OVqgSZVl3HukJ0rCh025UCNWO01lB3mvCGNwpb4NCymtD0pwSg4rytWKuA6xp4Q-lJ9nLvHa0L8pBYkGWKoeakFDwRZ3tCO7iUozc9-D_SgZHXC85vJfjJKIuS1qqGVqhClS1rRAlMaN02JVG6qRQRyXW-d4VfOMZ2YbNxTKNNQwaUUFElCs4lY7WSDLGRLRVc6kojJ6iF5ph07w8fH9setcJh8mAX1uWTwezk1l3JilBe1kUSvDkIvPsZMUyyN2HeKRjQxesYqlIUjM4xvPoHvT-sA7WFlIcZOpfeq2apPBWk4TWjTZWo9T1UujT2RqXT2pm0vih4uyhIzIS_py3EEOTZ1y__z178WLKv77A7BDvtgrNxPrRhCbI9qLwLwWN3GzIp5NxsN2nIudnkodlS2Yu7G3RbdNNd9C-voSdu</recordid><startdate>20200406</startdate><enddate>20200406</enddate><creator>Piel, Sarah</creator><creator>Chamkha, Imen</creator><creator>Dehlin, Adam Kozak</creator><creator>Ehinger, Johannes K</creator><creator>Sjövall, Fredrik</creator><creator>Elmér, Eskil</creator><creator>Hansson, Magnus J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AGCHP</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D95</scope><scope>ZZAVC</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2417-5767</orcidid><orcidid>https://orcid.org/0000-0001-5612-0325</orcidid><orcidid>https://orcid.org/0000-0002-1779-3532</orcidid></search><sort><creationdate>20200406</creationdate><title>Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose</title><author>Piel, Sarah ; Chamkha, Imen ; Dehlin, Adam Kozak ; Ehinger, Johannes K ; Sjövall, Fredrik ; Elmér, Eskil ; Hansson, Magnus J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c761t-ff4f06f400dbf26ed4438da8fd15959ceba5ab48131931aa755b74bca5d8a5933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetaminophen</topic><topic>Acetylcysteine</topic><topic>Analgesics</topic><topic>Analysis</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Automation</topic><topic>Basic Medicine</topic><topic>Biology and Life Sciences</topic><topic>Blood platelets</topic><topic>Care and treatment</topic><topic>Cells (Biology)</topic><topic>Characterization</topic><topic>Chemical compounds</topic><topic>Drug dosages</topic><topic>Drug therapy</topic><topic>Drugs</topic><topic>EDTA</topic><topic>Electron transport chain</topic><topic>Farmakologi och toxikologi</topic><topic>Health aspects</topic><topic>Hepatocytes</topic><topic>Injuries</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Liver failure</topic><topic>Medical and Health Sciences</topic><topic>Medical research</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>Mitochondria</topic><topic>NADH</topic><topic>Nicotinamide adenine dinucleotide</topic><topic>Nonprescription drugs</topic><topic>Novels</topic><topic>Overdose</topic><topic>Oxidative stress</topic><topic>Pain</topic><topic>Permeability</topic><topic>Pharmaceuticals</topic><topic>Pharmacology and Toxicology</topic><topic>Phosphorylation</topic><topic>Prodrugs</topic><topic>Respiration</topic><topic>Therapeutic applications</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Piel, Sarah</creatorcontrib><creatorcontrib>Chamkha, Imen</creatorcontrib><creatorcontrib>Dehlin, Adam Kozak</creatorcontrib><creatorcontrib>Ehinger, Johannes K</creatorcontrib><creatorcontrib>Sjövall, Fredrik</creatorcontrib><creatorcontrib>Elmér, Eskil</creatorcontrib><creatorcontrib>Hansson, Magnus J</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Piel, Sarah</au><au>Chamkha, Imen</au><au>Dehlin, Adam Kozak</au><au>Ehinger, Johannes K</au><au>Sjövall, Fredrik</au><au>Elmér, Eskil</au><au>Hansson, Magnus J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-04-06</date><risdate>2020</risdate><volume>15</volume><issue>4</issue><spage>e0231173</spage><epage>e0231173</epage><pages>e0231173-e0231173</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32251487</pmid><doi>10.1371/journal.pone.0231173</doi><tpages>e0231173</tpages><orcidid>https://orcid.org/0000-0002-2417-5767</orcidid><orcidid>https://orcid.org/0000-0001-5612-0325</orcidid><orcidid>https://orcid.org/0000-0002-1779-3532</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-04, Vol.15 (4), p.e0231173-e0231173 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2386851265 |
| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acetaminophen Acetylcysteine Analgesics Analysis Antioxidants Antioxidants (Nutrients) Automation Basic Medicine Biology and Life Sciences Blood platelets Care and treatment Cells (Biology) Characterization Chemical compounds Drug dosages Drug therapy Drugs EDTA Electron transport chain Farmakologi och toxikologi Health aspects Hepatocytes Injuries Liver Liver diseases Liver failure Medical and Health Sciences Medical research Medicin och hälsovetenskap Medicine Medicine and Health Sciences Medicinska och farmaceutiska grundvetenskaper Mitochondria NADH Nicotinamide adenine dinucleotide Nonprescription drugs Novels Overdose Oxidative stress Pain Permeability Pharmaceuticals Pharmacology and Toxicology Phosphorylation Prodrugs Respiration Therapeutic applications Toxicity |
| title | Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T01%3A38%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cell-permeable%20succinate%20prodrugs%20rescue%20mitochondrial%20respiration%20in%20cellular%20models%20of%20acute%20acetaminophen%20overdose&rft.jtitle=PloS%20one&rft.au=Piel,%20Sarah&rft.date=2020-04-06&rft.volume=15&rft.issue=4&rft.spage=e0231173&rft.epage=e0231173&rft.pages=e0231173-e0231173&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0231173&rft_dat=%3Cgale_plos_%3EA619584397%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2386851265&rft_id=info:pmid/32251487&rft_galeid=A619584397&rft_doaj_id=oai_doaj_org_article_38c8ab6c0c2b4962a46ddb921cd97c16&rfr_iscdi=true |