Purified acetaminophen-glutathione conjugate is able to induce oxidative stress in rat liver mitochondria
Language English Country Czech Republic Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
23130894
DOI
10.33549/physiolres.932427
PII: 932427
Knihovny.cz E-resources
- MeSH
- Mitochondria, Liver drug effects metabolism MeSH
- Liver metabolism MeSH
- Rats MeSH
- Glutamic Acid metabolism MeSH
- Chemical and Drug Induced Liver Injury metabolism pathology MeSH
- Malates metabolism MeSH
- Disease Models, Animal MeSH
- Oxidative Stress * MeSH
- Acetaminophen analogs & derivatives chemical synthesis isolation & purification toxicity MeSH
- Rats, Wistar MeSH
- Reactive Oxygen Species metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-(glutathion-S-yl)acetaminophen MeSH Browser
- Glutamic Acid MeSH
- Malates MeSH
- malic acid MeSH Browser
- Acetaminophen MeSH
- Reactive Oxygen Species MeSH
Acetaminophen overdose is the most often cause of acute liver injury. The toxic mechanism is linked to formation of an active metabolite that reacts with glutathione generating acetaminophen-glutathione conjugate (APAP-SG). This compound has been recognized to be non-toxic generally. Our preliminary results showed, however, that APAP-SG could possess a toxic effect too. Therefore, the aim of our study was to prepare, purify and to test possible toxicity of APAP-SG. We prepared APAP-SG using organic synthesis. The conjugate was purified by preparative HPLC and its structure was confirmed using mass spectrometry. Final purity of APAP-SG was >98 %. We estimated a toxic effect of APAP-SG in isolated rat liver mitochondria using a fluorescent ROS probe. We assessed ROS production in presence of complex I or complex II substrates. The increase of ROS-dependent fluorescence in presence of glutamate/malate was 104 ± 13 % and 130 ± 10 % in 1 mM and 5 mM APAP-SG, respectively, in comparison with controls. ROS production related to presence of complex II substrate was enhanced 4-times in APAP-SG (5 mM) treated mitochondria (compared to controls). We conclude, we proved our hypothesis that APAP-SG conjugate is able to induce a mitochondrial impairment leading to enhanced ROS production.
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