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Propyl gallate-induced DNA fragmentation in isolated rat hepatocytes
Y Nakagawa1, P Moldéus, G Moore
1Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Archives of Toxicology
|January 1, 1997
Summary
Propyl gallate (PG) at high concentrations causes rat hepatocyte death, while lower concentrations induce apoptosis. N-acetylcysteine protects cells by preventing DNA fragmentation and glutathione depletion.
Area of Science:
- Hepatocyte toxicology
- Cellular apoptosis mechanisms
- Antioxidant effects on cell death
Background:
- Propyl gallate (PG) is a compound with potential applications, but its toxicological profile on liver cells requires detailed investigation.
- Understanding the mechanisms of cell death induced by xenobiotics is crucial for assessing their safety and potential therapeutic uses.
Purpose of the Study:
- To investigate the dose-dependent effects of propyl gallate (PG) on isolated rat hepatocytes.
- To elucidate the specific mode of cell death (necrosis vs. apoptosis) induced by PG.
- To explore the role of glutathione (GSH) and N-acetylcysteine in modulating PG-induced hepatotoxicity.
Main Methods:
- Incubation of isolated rat hepatocytes with varying concentrations of propyl gallate (PG).
- Assessment of cell viability and identification of apoptosis markers, including DNA fragmentation (ladder formation) and nuclear DNA cleavage.
- Measurement of cellular glutathione (GSH) and ATP levels, and observation of cell morphology changes like blebbing.
- Evaluation of the protective effects of N-acetylcysteine pretreatment against PG-induced cellular damage.
Main Results:
- Propyl gallate (PG) at concentrations >= 1 mM induced significant cell killing (necrosis).
- PG at concentrations <= 0.5 mM triggered characteristic apoptotic features, including DNA fragmentation and nuclear cleavage.
- N-acetylcysteine pretreatment prevented PG-induced DNA fragmentation, GSH depletion, ATP loss, and blebbing, indicating an antioxidant protective role.
- The onset of DNA fragmentation was closely associated with cellular glutathione (GSH) depletion.
Conclusions:
- Hepatocyte response to propyl gallate (PG) shifts from necrosis to apoptosis as concentration decreases.
- Glutathione (GSH) depletion plays a critical role in mediating PG-induced DNA fragmentation and apoptosis in hepatocytes.
- N-acetylcysteine, as a glutathione precursor, effectively mitigates propyl gallate-induced cellular damage, highlighting the importance of antioxidant defense.