The toxic effect of thioacetamide on rat liver in vitro
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20600801
DOI
10.1016/j.tiv.2010.06.011
PII: S0887-2333(10)00153-0
Knihovny.cz E-resources
- MeSH
- Hepatocytes drug effects metabolism MeSH
- Liver drug effects metabolism MeSH
- Rats MeSH
- Cells, Cultured MeSH
- L-Lactate Dehydrogenase metabolism MeSH
- Chemical and Drug Induced Liver Injury metabolism MeSH
- Malondialdehyde metabolism MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Hazardous Substances toxicity MeSH
- Oxidative Stress MeSH
- Rats, Wistar MeSH
- Reactive Oxygen Species metabolism MeSH
- Thioacetamide toxicity 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
- L-Lactate Dehydrogenase MeSH
- Malondialdehyde MeSH
- Hazardous Substances MeSH
- Reactive Oxygen Species MeSH
- Thioacetamide MeSH
Thioacetamide (TAA) is a hepatotoxin frequently used for experimental purposes which produces centrilobular necrosis after a single dose administration. In spite of the fact that oxidative stress seems to play a very important role in the mechanism of TAA-induced injury, the effect of TAA on hepatocytes in primary culture with respect to the influence on mitochondria has yet to be verified. Hepatocytes were incubated for 24h in a medium containing TAA (0-70 mmol/l). Glutathione content (GSH/GSSG), reactive oxygen species and malondialdehyde formation were assessed as markers of cell redox state. Toxicity was determined by lactate dehydrogenase leakage and WST-1 assay. The functional capacity of hepatocytes was evaluated from albumin and urea production. Mitochondrial metabolism was assessed by measuring mitochondrial membrane potential and oxygen consumption. Our results show that a profound decrease in the GSH level in hepatocytes precedes a sharp rise in endogenous ROS production. ROS production correlates with an increase in lipoperoxidation. Mitochondria are affected by TAA secondarily as a consequence of oxidative stress. Oxidation of the NADH-dependent substrates of respiratory Complex I is significantly more sensitive to the toxic action of TAA than oxidation of the flavoprotein-dependent substrate of Complex II. Mitochondria can also maintain their membrane potential better when they utilize succinate as a respiratory substrate. It appears that GSH should be depleted below a certain critical level in order to cause a marked increase in lipid peroxidation. Mitochondrial injury can then occur and cell death develops.
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