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Nephrotoxins: widespread role of oxidative stress and electron transfer
Peter Kovacic1, Aileen Sacman, Mae Wu-Weis
1Department of Chemistry, San Diego State University, San Diego, CA 92182-1030, USA. pkovacic@sundown.sdsu.edu
Abstract:
Kidney toxicity comprises an important type of hospital admission with associated high costs. Large numbers of chemicals are involved comprising a wide variety of classes, both organic and inorganic. These include therapeutic drugs, radiocontrast agents, carcinogens, metals, abused drugs, and industrial chemicals. This review provides extensive evidence for participation of oxidative stress (OS) and electron transfer (ET) as a unifying framework. Application is made to all the main classes of nephrotoxins, in addition to many miscellaneous types. We believe it is not coincidental that the vast majority of these substances incorporate ET functionalities (quinone, metal complex, ArNO2, or conjugated iminium) either per se or in metabolites, potentially giving rise to reactive oxygen species (ROS) by redox cycling. Some categories, e.g., radiation, radiocontrast agents, and peroxides, appear to generate OS by non-ET routes. For completeness, other theories are also addressed; a multifaceted approach appears the most logical. The ET-OS viewpoint should increase understanding and contribute to prevention, e.g., use of antioxidants.
Insights
Kidney toxicity from various chemicals is linked to oxidative stress (OS) and electron transfer (ET). Understanding these mechanisms, particularly ET functionalities, can help prevent kidney damage using antioxidants.
Area of Science:
- Toxicology
- Biochemistry
- Nephrology
Background:
- Kidney toxicity is a significant cause of hospital admissions with high costs.
- Numerous organic and inorganic chemicals, including drugs, metals, and industrial agents, can cause nephrotoxicity.
- Existing knowledge on nephrotoxin mechanisms is diverse and lacks a unifying framework.
Purpose of the Study:
- To review and present evidence for oxidative stress (OS) and electron transfer (ET) as a unifying mechanism in chemical-induced kidney toxicity.
- To apply the ET-OS framework to various classes of nephrotoxins.
- To explore alternative mechanisms and advocate for a multifaceted approach to understanding nephrotoxicity.
Main Methods:
- Comprehensive literature review of chemical nephrotoxins and their mechanisms of action.
- Analysis of chemical structures and metabolic pathways for electron transfer functionalities.
- Evaluation of evidence supporting oxidative stress generation via redox cycling.
- Consideration of non-ET pathways for OS induction.
Main Results:
- Extensive evidence supports the involvement of OS and ET in the nephrotoxicity of most chemical classes.
- Many nephrotoxins, or their metabolites, possess ET functionalities (e.g., quinones, metal complexes) that can generate reactive oxygen species (ROS) via redox cycling.
- Certain agents like radiation, radiocontrast agents, and peroxides may induce OS through non-ET pathways.
Conclusions:
- The electron transfer-oxidative stress (ET-OS) framework provides a unifying perspective on chemical-induced kidney toxicity.
- Recognizing ET functionalities in nephrotoxins is crucial for understanding their detrimental effects.
- This viewpoint can guide the development of preventive strategies, such as the use of antioxidants, and supports a multifaceted approach to nephrotoxicity research.