Related Experiment Video
Updated: Sep 21, 2026
Assessment of Endothelial Cell Migration After Exposure to Toxic Chemicals
Published on: July 10, 2015
Mitochondrial dysfunction is an early manifestation of 1,1-dichloroethylene-induced hepatotoxicity in mice
Erik J Martin1, William J Racz, Poh-Gek Forkert
1Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
Abstract:
Hepatotoxicity induced by 1,1-dichloroethylene (DCE) is mediated by cytochrome P450-dependent metabolism to reactive intermediates, including the epoxide. We have tested the hypothesis that mitochondria are a primary target of toxicity by investigating dose- and time-dependent effects of DCE on mitochondrial respiration. Hepatotoxicity, as assessed by serum alanine aminotransferase (ALT) activity, was evaluated. We have also determined the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory perturbations and hepatotoxicity. Liver mitochondria were isolated 2 h after DCE (50, 75, 100, 125, and 150 mg/kg) treatment. Glutamate (complex I)- and succinate (complex II)-supported mitochondrial respiration was assessed by measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption. The corresponding respiratory control ratios (RCRs, state 3/state 4) and ADP:O ratios were then calculated. A DCE dose of 125 mg/kg significantly inhibited glutamate- and succinate-supported state 3 respiration, leading to a significant reduction in corresponding RCRs and ADP:O ratios. In time-dependent studies, state 3 respiration rates and RCRs for glutamate-supported respiration were significantly decreased as early as 20 min after DCE (125 mg/kg) treatment, whereas those for succinate-supported respiration were significantly decreased at 90 min. Additionally, ADP:O ratios for glutamate-supported respiration were significantly decreased starting at 60 min, and those for succinate-supported respiration at 90 min. Alterations in mitochondrial function preceded significant increases in ALT activity, which was first manifested at 2 h. Pretreatment with NAC (1200 mg/kg) abrogated DCE-induced GSH depletion and inhibited disturbances in mitochondrial respiration. Moreover, NAC protected against increased ALT activity, suggesting that the protective effect of NAC is due to increased GSH for conjugation reactions and/or its antioxidant property. These results showed that DCE-mediated mitochondrial dysfunction is an early event that preceded the onset of hepatotoxicity.
Insights
1,1-dichloroethylene (DCE) causes liver damage by disrupting mitochondrial respiration. N-acetyl-L-cysteine (NAC) protects against this toxicity by preserving mitochondrial function and reducing liver injury.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Hepatotoxicity from 1,1-dichloroethylene (DCE) involves P450 metabolism to reactive intermediates.
- Mitochondria are potential targets for DCE-induced cellular damage.
Purpose of the Study:
- To investigate the dose- and time-dependent effects of DCE on mitochondrial respiration.
- To assess the protective role of N-acetyl-L-cysteine (NAC) against DCE-induced hepatotoxicity and mitochondrial dysfunction.
Main Methods:
- Isolated rat liver mitochondria were used to measure respiration (state 3 and 4), respiratory control ratios (RCRs), and ADP:O ratios after DCE administration.
- Hepatotoxicity was assessed by serum alanine aminotransferase (ALT) activity.
- The impact of NAC pretreatment on DCE effects was evaluated.
Main Results:
- DCE significantly inhibited mitochondrial respiration (state 3), RCRs, and ADP:O ratios in a dose-dependent manner.
- Mitochondrial dysfunction occurred as early as 20-90 minutes post-DCE exposure, preceding significant increases in ALT activity at 2 hours.
- NAC pretreatment prevented DCE-induced glutathione depletion, mitochondrial respiratory disturbances, and elevated ALT levels.
Conclusions:
- Mitochondrial dysfunction is an early event in 1,1-dichloroethylene-induced hepatotoxicity.
- N-acetyl-L-cysteine demonstrates protective effects against DCE toxicity, likely through glutathione restoration and antioxidant mechanisms.
