Chen-yuan Liao , Xiao-lei Yi , Yu-xin Yang , Jia-min Gong , Yu-Lin Ma , Fei Long , Zhen-zhong Liu , Zuo Du
{"title":"氨基甲酸酯类农药对人羧酸酯酶抑制作用的评价。","authors":"Chen-yuan Liao , Xiao-lei Yi , Yu-xin Yang , Jia-min Gong , Yu-Lin Ma , Fei Long , Zhen-zhong Liu , Zuo Du","doi":"10.1016/j.taap.2025.117454","DOIUrl":null,"url":null,"abstract":"<div><div>Carbamate pesticides (CMs), which are widely applied in agricultural production and living environments, have been confirmed to exhibit disruptive effects on lipid metabolism as environmental endocrine disruptors. The present study aims to investigate the inhibition behavior of CMs on the activity of the critical hydrolytic enzymes, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), to elucidate the toxicity mechanisms from a novel perspective. Based on network toxicology analysis, CESs were identified as potential targets for CMs-induced lipid metabolism disorders. <em>In vitro</em> incubation experiments demonstrated that most CMs strongly inhibited the activity of CES1 and CES2, with inhibition ratios exceeding 80 %. Kinetic studies and <em>in vitro-in vivo</em> extrapolation revealed that CMs might disrupt the metabolic homeostasis of lipids by inhibiting CESs <em>in vivo</em>. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of CMs towards CESs. Cellular fluorescence imaging confirmed the inhibition of CMs on CESs in HepG2 cells. These findings provide new experimental evidence for understanding the mechanism of CMs-mediated lipid metabolism disorders through inhibition on CESs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117454"},"PeriodicalIF":3.3000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of the inhibitory effects of carbamate pesticides on human carboxylesterases\",\"authors\":\"Chen-yuan Liao , Xiao-lei Yi , Yu-xin Yang , Jia-min Gong , Yu-Lin Ma , Fei Long , Zhen-zhong Liu , Zuo Du\",\"doi\":\"10.1016/j.taap.2025.117454\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Carbamate pesticides (CMs), which are widely applied in agricultural production and living environments, have been confirmed to exhibit disruptive effects on lipid metabolism as environmental endocrine disruptors. The present study aims to investigate the inhibition behavior of CMs on the activity of the critical hydrolytic enzymes, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), to elucidate the toxicity mechanisms from a novel perspective. Based on network toxicology analysis, CESs were identified as potential targets for CMs-induced lipid metabolism disorders. <em>In vitro</em> incubation experiments demonstrated that most CMs strongly inhibited the activity of CES1 and CES2, with inhibition ratios exceeding 80 %. Kinetic studies and <em>in vitro-in vivo</em> extrapolation revealed that CMs might disrupt the metabolic homeostasis of lipids by inhibiting CESs <em>in vivo</em>. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of CMs towards CESs. Cellular fluorescence imaging confirmed the inhibition of CMs on CESs in HepG2 cells. These findings provide new experimental evidence for understanding the mechanism of CMs-mediated lipid metabolism disorders through inhibition on CESs.</div></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":\"502 \",\"pages\":\"Article 117454\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X25002303\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X25002303","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Evaluation of the inhibitory effects of carbamate pesticides on human carboxylesterases
Carbamate pesticides (CMs), which are widely applied in agricultural production and living environments, have been confirmed to exhibit disruptive effects on lipid metabolism as environmental endocrine disruptors. The present study aims to investigate the inhibition behavior of CMs on the activity of the critical hydrolytic enzymes, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), to elucidate the toxicity mechanisms from a novel perspective. Based on network toxicology analysis, CESs were identified as potential targets for CMs-induced lipid metabolism disorders. In vitro incubation experiments demonstrated that most CMs strongly inhibited the activity of CES1 and CES2, with inhibition ratios exceeding 80 %. Kinetic studies and in vitro-in vivo extrapolation revealed that CMs might disrupt the metabolic homeostasis of lipids by inhibiting CESs in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of CMs towards CESs. Cellular fluorescence imaging confirmed the inhibition of CMs on CESs in HepG2 cells. These findings provide new experimental evidence for understanding the mechanism of CMs-mediated lipid metabolism disorders through inhibition on CESs.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.