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Allyl alcohol toxicity in isolated renal epithelial cells: protective effects of low molecular weight thiols
Abstract:
The toxicity of allyl alcohol was studied in freshly isolated renal epithelial cells prepared from male and female rats. Cells from female rats demonstrated a greater susceptibility to allyl alcohol toxicity as assessed by glutathione depletion and loss of cell viability. The sensitivity of female rat renal cells appears to relate to the higher activity of alcohol dehydrogenase found in the female rat kidney, which metabolizes allyl alcohol to the highly reactive aldehyde, acrolein. Pyrazole, an inhibitor of alcohol dehydrogenase, abolished the cytotoxic effects of allyl alcohol whereas inhibition of aldehyde dehydrogenase by disulfiram treatment was found to increase the sensitivity of renal cells to the effects of allyl alcohol. The toxicity of allyl alcohol was decreased by a number of treatments which resulted in increased levels of glutathione or other low molecular weight thiols. These results indicate that acrolein is the toxic metabolite responsible for the renal cell injury following exposure to allyl alcohol, and unless immediately inactivated acrolein interacts with critical nucleophilic sites of the cell and initiates cell injury. These studies demonstrate that freshly isolated kidney cells represent a convenient model system for studies of thiol-mediated protective mechanisms against toxic renal cell injury.
Insights
Female rat kidney cells are more vulnerable to allyl alcohol toxicity due to higher alcohol dehydrogenase activity, leading to acrolein formation. Thiol treatments protect against this renal cell injury.
Area of Science:
- Toxicology
- Renal Cell Biology
- Biochemistry
Background:
- Allyl alcohol is a known toxicant.
- Renal epithelial cells are targets for chemical injury.
- Understanding mechanisms of chemical toxicity is crucial for risk assessment.
Purpose of the Study:
- To investigate the differential toxicity of allyl alcohol in male and female rat renal cells.
- To identify the toxic metabolite of allyl alcohol in kidney cells.
- To explore thiol-mediated protective mechanisms against allyl alcohol-induced renal injury.
Main Methods:
- Isolation and culture of primary renal epithelial cells from male and female rats.
- Assessment of cell viability and glutathione levels.
- Enzyme inhibition studies using pyrazole (alcohol dehydrogenase inhibitor) and disulfiram (aldehyde dehydrogenase inhibitor).
Main Results:
- Female rat renal cells exhibited higher susceptibility to allyl alcohol toxicity, evidenced by greater glutathione depletion and loss of cell viability.
- Higher alcohol dehydrogenase activity in female rat kidneys metabolizes allyl alcohol to acrolein, the toxic aldehyde.
- Pyrazole treatment abolished allyl alcohol's cytotoxic effects, while disulfiram increased sensitivity.
- Treatments increasing glutathione or thiol levels reduced allyl alcohol toxicity.
Conclusions:
- Acrolein is the primary toxic metabolite responsible for allyl alcohol-induced renal cell injury.
- Thiol-mediated detoxification is a critical protective mechanism against acrolein toxicity.
- Freshly isolated kidney cells provide a valuable model for studying thiol-dependent protection against renal toxicants.