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1,1-Dichloroethylene elicits dose-dependent alterations in covalent binding and glutathione in murine liver
1Department of Anatomy, Queen's University, Kingston, Ontario, Canada.
Abstract:
Dose-response studies have been performed using the hepatotoxin 1,1-dichloroethylene (1,1-DCE) to investigate effects of its administration on covalent binding, content of reduced glutathione (GSH), and structural alterations in murine liver. Additionally, these studies have determined if the sites of cellular damage coincided preferentially with the sites of GSH depletion. Treatment with 1,1-DCE evoked dose-dependent alterations in both covalent binding and tissue GSH content. Progressive increases in covalent binding (2.8 +/- 0.8 to 12.5 +/- 1.9 nmol/mg protein) were found within the range of doses tested (75-225 mg/kg). Tissue GSH content (86.4 +/- 6.1 to 35.9 +/- 2.4 nmol/mg protein) declined significantly after 1,1-DCE treatment when compared to that in control mice (128.0 +/- 3.6 nmol/mg protein). Alterations in GSH content due to 1,1-DCE treatment included those associated with significant increases (34-81% of control) in blood volume. Concomitant increases in vascular GSH were observed, and at 225 mg/kg, GSH content comprised 190% of that found in controls. Histochemical staining for GSH exhibited dose-related decreases in staining intensities that were not concentrated in any particular region, but, rather, were uniformly distributed throughout the liver lobule. Liver injury involving centrilobular and midzonal hepatocytes was absent at 75 mg/kg, mild at 125 and 175 mg/kg, and was most severe at 225 mg/kg. The results from these experiments demonstrate dose-dependent relationships between the magnitude of covalent binding of 1,1-DCE metabolite(s), diminished levels of tissue GSH, and hepatocellular necrosis.
Insights
Hepatotoxin 1,1-dichloroethylene (1,1-DCE) causes dose-dependent liver damage by increasing covalent binding and depleting reduced glutathione (GSH) in mice. Cellular injury and GSH depletion occurred uniformly across liver lobules.
Area of Science:
- Hepatotoxicity and Toxicology
- Biochemistry
- Cellular Pathology
Background:
- Hepatotoxin 1,1-dichloroethylene (1,1-DCE) is known to cause liver damage.
- Understanding the dose-response relationship is crucial for assessing toxicity.
- Reduced glutathione (GSH) plays a protective role in the liver against toxic insults.
Purpose of the Study:
- To investigate the dose-dependent effects of 1,1-DCE on covalent binding, GSH content, and liver structure in mice.
- To determine if sites of cellular damage correlate with sites of GSH depletion.
- To elucidate the relationship between 1,1-DCE exposure, GSH levels, and hepatocellular necrosis.
Main Methods:
- Administration of varying doses of 1,1-DCE (75-225 mg/kg) to mice.
- Quantification of covalent binding of 1,1-DCE metabolites to liver proteins.
- Measurement of hepatic reduced glutathione (GSH) content.
- Histochemical staining for GSH distribution.
- Histopathological examination of liver tissue for signs of injury.
Main Results:
- 1,1-DCE administration resulted in a dose-dependent increase in covalent binding and a significant decrease in hepatic GSH levels.
- GSH depletion was uniformly distributed throughout the liver lobule, not localized to specific regions.
- Hepatocellular injury, particularly centrilobular and midzonal necrosis, showed a dose-dependent severity, correlating with higher doses of 1,1-DCE.
- Increased blood volume and vascular GSH were observed at higher doses.
Conclusions:
- A clear dose-dependent relationship exists between 1,1-DCE exposure, covalent binding of its metabolites, and depletion of hepatic GSH.
- Hepatocellular necrosis severity is directly related to the dose of 1,1-DCE administered.
- The findings suggest that widespread GSH depletion contributes to the observed liver injury, with damage not confined to specific lobular regions.