CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Chemical Research in Toxicology Pub Date : 2024-06-17 DOI:10.1021/acs.chemrestox.3c00351

Xinxin Guo, Mingyu Zhang, Ya Li, Zifang Ding, Minglu Liu, Weiwei Li*, Ying Peng* and Jiang Zheng*,

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Abstract

Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.

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CYP3A4介导的代谢活化和氯酯脲的细胞毒性

灭草隆（CTU）是一种除草剂，广泛用于农业作物栽培。它在水中的存在已被确认为对水生物种有害的污染物。本研究旨在探讨 CTU 的代谢活化和肝毒性。在加入 CTU、烟酰胺腺嘌呤二核苷酸磷酸酯（NADPH）和谷胱甘肽或 N-乙酰半胱氨酸的人和大鼠肝脏微粒体培养液中，发现了苯甲醇代谢物（M1）以及苯酚代谢物（M2）、谷胱甘肽共轭物（M3）和 N-乙酰半胱氨酸共轭物（M4）。暴露于 CTU 的大鼠的胆汁和尿液中分别检测到胆汁 M3 和尿液 M4。在 NADPH 存在的情况下可检测到 M1 的生成。对 M3 和 M4 的观察表明，M1 氧化后会形成亚氨基醌甲酰胺中间体。研究发现，CYP3A4 是催化 CTU 代谢活化的主要酶。此外，CTU 在培养的大鼠原代肝细胞中表现出细胞毒性特性，且呈浓度依赖性。同时用酮康唑处理肝细胞可减轻它们对 CTU 细胞毒性作用的敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Research in Toxicology 医学-毒理学

CiteScore

7.90

自引率

7.30%

发文量

215

审稿时长

3.5 months

期刊介绍： Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.

文献相关原料

公司名称

产品信息

麦克林

2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)

阿拉丁

Glutathione (GSH)