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Systematic health risks assessment of chiral fungicide famoxadone: Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior.

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العنوان: Systematic health risks assessment of chiral fungicide famoxadone: Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior.
المؤلفون: Xiao S; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Cui J; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Yang J; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Hou H; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Yao J; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Ma X; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Zheng L; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Zhao F; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Liu X; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Liu D; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Zhou Z; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China., Wang P; Beijing Advanced Innovation Centre for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, No.2 West Yuanmingyuan Road, Beijing 100193, PR China. Electronic address: wangpeng@cau.edu.cn.
المصدر: Journal of hazardous materials [J Hazard Mater] 2024 Sep 15; Vol. 477, pp. 135199. Date of Electronic Publication: 2024 Jul 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9422688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3336 (Electronic) Linking ISSN: 03043894 NLM ISO Abbreviation: J Hazard Mater Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier,
مواضيع طبية MeSH: Fungicides, Industrial*/toxicity , Fungicides, Industrial*/chemistry , Ferroptosis*/drug effects , Strobilurins*/toxicity , Strobilurins*/chemistry, Animals ; Humans ; Hep G2 Cells ; Stereoisomerism ; Risk Assessment ; Molecular Docking Simulation ; Mice ; Male ; Cytochrome P-450 Enzyme System/metabolism ; Reactive Oxygen Species/metabolism ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Lipid Peroxidation/drug effects ; Cell Survival/drug effects
مستخلص: Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Cytochrome P450; Cytotoxicity; Famoxadone; Ferroptosis; Stereoselective
المشرفين على المادة: 0 (Fungicides, Industrial)
0 (Strobilurins)
V1C07OR6II (famoxadone)
9035-51-2 (Cytochrome P-450 Enzyme System)
0 (Reactive Oxygen Species)
تواريخ الأحداث: Date Created: 20240725 Date Completed: 20240816 Latest Revision: 20240816
رمز التحديث: 20240816
DOI: 10.1016/j.jhazmat.2024.135199
PMID: 39053069
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-3336
DOI:10.1016/j.jhazmat.2024.135199