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Toxicity of cisplatin and mercuric chloride in human kidney cortical slices
R L Fisher1, J T Sanuik, A J Gandolfi
1Department of Pharmacology, University of Arizona, Tucson 85724.
Abstract:
1. Organ specific toxicity such as nephrotoxicity is often investigated with the use of in vivo or in vitro animal models. 2. It would be beneficial if these findings could be verified in a human in vitro system which utilizes non-transplantable human kidneys. 3. Non-transplantable human kidneys were decapsulated, cut in half along the long axis, cores made perpendicular to the hemisphere, and precision-cut renal cortical slices produced. 4. These human kidney slices were incubated for 3, 6, 12, 18 and 24 h, viability assessed using intracellular K+ content, protein synthesis and organic ion transport and the potential nephrotoxicity of cisplatin (0.25, 0.5 and 1.0 mM) and mercuric chloride (10, 50 and 100 microM) on these slices were examined. 5. Control human kidney slices were viable for up to 24 h using all viability parameters while a dose- and time-dependent toxic response was seen using both cisplatin and mercuric chloride. 6. Cisplatin was more nephrotoxic in this human in vitro system than in previously investigated in vitro animal systems whereas mercuric chloride was similar in both systems. 7. These results indicate that human renal cortical slices are useful in predicting and verifying potentially nephrotoxic compounds in man.
Insights
This study developed a human in vitro model using kidney slices to test drug toxicity. The human renal cortical slices accurately predicted the nephrotoxicity of cisplatin and mercuric chloride in humans.
Area of Science:
- Nephrology
- Toxicology
- In Vitro Models
Background:
- Organ-specific toxicity, like nephrotoxicity, is typically studied using animal models.
- A human in vitro system using non-transplantable kidneys is needed for verification.
Purpose of the Study:
- To establish and validate a human in vitro system for assessing nephrotoxicity.
- To evaluate the nephrotoxic potential of cisplatin and mercuric chloride in human kidney slices.
Main Methods:
- Non-transplantable human kidneys were processed into precision-cut renal cortical slices.
- Slices were incubated for up to 24 hours and assessed for viability using K+ content, protein synthesis, and organic ion transport.
- The nephrotoxicity of varying concentrations of cisplatin and mercuric chloride was examined.
Main Results:
- Human kidney slices remained viable for up to 24 hours.
- Both cisplatin and mercuric chloride demonstrated a dose- and time-dependent toxic response.
- Cisplatin showed higher nephrotoxicity in the human system compared to animal models, while mercuric chloride's toxicity was comparable.
Conclusions:
- Human renal cortical slices provide a viable and effective in vitro system for toxicity assessment.
- This model is valuable for predicting and verifying the nephrotoxicity of compounds in humans.
- The findings highlight the utility of human-derived tissue models in drug safety evaluation.