Potential Common Mechanisms of Cytotoxicity Induced by Amide Herbicides via TRPA1 Channel Activation

Xiaoning Wang, Yangyang Sun, Qian Wang, Fengying Liu, Weijie Yang, Xin Sui, Jun Yang, Minmin Zhang, Shuai Wang, Zhenyu Xiao, Yuan Luo, Yongan Wang and Tong Zhu
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Xiaoning Wang: Institute of Process Equipment and Environmental Engineering, School of Mechanical Engineering and Automation, Northeastern University, Shenyang 110819, China
Yangyang Sun: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Qian Wang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Fengying Liu: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Weijie Yang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Xin Sui: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Jun Yang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Minmin Zhang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Shuai Wang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Zhenyu Xiao: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Yuan Luo: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Yongan Wang: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Tong Zhu: Institute of Process Equipment and Environmental Engineering, School of Mechanical Engineering and Automation, Northeastern University, Shenyang 110819, China

IJERPH, 2022, vol. 19, issue 13, 1-18

Abstract: The “Multi-Threat Medical Countermeasure (MTMC)” strategy was proposed to develop a single drug with therapeutic efficacy against multiple pathologies or broad-spectrum protection against various toxins with common biochemical signals, molecular mediators, or cellular processes. This study demonstrated that cytotoxicity, expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) mRNA, and intracellular calcium influx were increased in A549 cells exposed to amide herbicides (AHs), in which the order of cytotoxicity was metolachlor > acetochlor > propisochlor > alachlor > butachlor > propanil > pretilachlor, based on IC 50 values of 430, 524, 564, 565, 619, 831, and 2333 μM, respectively. Inhibition/knockout of TRPA1 efficiently protected against cytotoxicity, decreased TRPA1 mRNA expression, and reduced calcium influx. The results suggested that the TRPA1 channel could be a key common target for AHs poisoning. The order of TRPA1 affinity for AHs was propanil > pretilachlor > metolachlor > (propiso/ala/aceto/butachlor), based on K D values of 16.2, 309, and 364 μM, respectively. The common molecular mechanisms of TRPA1-AHs interactions were clarified, including toxicity-effector groups (benzene ring, nitrogen/oxygen-containing functional groups, halogen) and residues involved in interactions (Lys787, Leu982). This work provides valuable information for the development of TRPA1 as a promising therapeutic target for broad-spectrum antitoxins.

Keywords: amide herbicides; TRPA1 channel; cytotoxicity; computational simulation; common mechanisms (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2022
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