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An integrated multiscale computational study of nephrotoxicity mechanism of citrinin and its metabolites
Jiaxing Li1, Furong Xue1, Linlin Xu1
1Key Laboratory of Geriatric Nutrition and Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Ministry of Education, Beijing Technology and Business University, Beijing, 100048, China.
Abstract:
Citrinin is a common mycotoxin found in food and poses risks to both human and animal health. While extensive research has been conducted on the nephrotoxicity of citrinin itself, the nephrotoxicity of its metabolites remains unclear. Therefore, this study investigated the nephrotoxic mechanism of citrinin and its metabolites (CIMs) using density functional theory, network toxicology, and computer simulations. Our findings revealed that CIMs also have potential toxicity, such as nephrotoxicity. Density functional theory explained the structural basis of the toxicity of CIMs. A total of 255 targets related to nephrotoxicity induced by CIMs were predicted by network toxicology. Notably, the enrichment results indicated the importance of multiple forms of programmed cell death in CIMs-induced nephrotoxicity. In addition, four key targets (TP53, MAPK1, MAPK3, and HSP90AA1) were identified, with molecular dynamics simulations validating stable binding between the four targets and CIMs. Van der Waals forces were the main driving force for stabilizing complexes formed between CIMs and the four targets through the binding free energy and independent gradient model analysis. Our research provides the theoretical basis and new insights for an in-depth study of the nephrotoxicity mechanism of CIMs and offers a new paradigm/approach for investigating the toxicity mechanism of other mycotoxins in the future.
Insights
Citrinin metabolites (CIMs) also cause kidney toxicity. Computational methods revealed CIMs bind to key targets like TP53, impacting cell death pathways and providing insights into mycotoxin nephrotoxicity.
Area of Science:
- Toxicology
- Computational Chemistry
- Molecular Biology
Background:
- Citrinin is a prevalent food mycotoxin with known health risks.
- The nephrotoxicity of citrinin metabolites (CIMs) is not well understood.
- Investigating CIMs' toxicity is crucial for food safety and health risk assessment.
Purpose of the Study:
- To elucidate the nephrotoxic mechanisms of citrinin metabolites (CIMs).
- To identify key molecular targets and pathways involved in CIMs-induced nephrotoxicity.
- To establish a computational approach for studying mycotoxin toxicity.
Main Methods:
- Density functional theory (DFT) for structural analysis of CIM toxicity.
- Network toxicology to predict targets related to CIM-induced nephrotoxicity.
- Computer simulations, including molecular dynamics (MD), for target-ligand interactions.
Main Results:
- CIMs exhibit potential nephrotoxicity, with DFT explaining their structural toxicity basis.
- Network toxicology identified 255 nephrotoxicity-related targets for CIMs.
- Key targets (TP53, MAPK1, MAPK3, HSP90AA1) showed stable binding with CIMs via Van der Waals forces, highlighting programmed cell death pathways.
Conclusions:
- CIMs possess nephrotoxic potential, contributing to overall citrinin toxicity.
- Computational toxicology provides a robust framework for understanding CIM nephrotoxicity.
- This study offers novel insights into mycotoxin toxicity mechanisms and future research directions.
