Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China; School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China; Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China.
Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China.
Chemosphere. 2024 Jun;358:142249. doi: 10.1016/j.chemosphere.2024.142249. Epub 2024 May 3.
Chlorophenols (CPs) are a group of pollutants that pose a great threat to the environment, they are widely used in industrial and agricultural wastes, pesticides, herbicides, textiles, pharmaceuticals and plastics. Among CPs, pentachlorophenol was listed as one of the persistent organic pollutants (POPs) by the Stockholm convention. This study aims to identify the UDP-glucosyltransferase (UGT) isoforms involved in the metabolic elimination of CPs. CPs' mono-glucuronide was detected in the human liver microsomes (HLMs) incubation mixture with co-factor uridine-diphosphate glucuronic acid (UDPGA). HLMs-catalyzed glucuronidation metabolism reaction equations followed Michaelis-Menten or substrate inhibition type. Recombinant enzymes and chemical reagents inhibition experiments were utilized to phenotype the main UGT isoforms involved in the glucuronidation of CPs. UGT1A6 might be the major enzyme in the glucuronidation of mono-chlorophenol isomer. UGT1A1, UGT1A6, UGT1A9, UGT2B4 and UGT2B7 were the most important five UGT isoforms for metabolizing the di-chlorophenol and tri-chlorophenol isomers. UGT1A1 and UGT1A3 were the most important UGT isoforms in the catalysis of tetra-chlorophenol and pentachlorophenol isomers. Species differences were investigated using rat liver microsomes (RLMs), pig liver microsomes (PLMs), dog liver microsomes (DLMs), and monkey liver microsomes (MyLMs). All these results were helpful for elucidating the metabolic elimination and toxicity of CPs.
氯酚类（CPs）是一类对环境构成巨大威胁的污染物，它们广泛存在于工业和农业废物、农药、除草剂、纺织品、制药和塑料中。在 CPs 中，五氯酚被《斯德哥尔摩公约》列为持久性有机污染物（POPs）之一。本研究旨在确定参与 CPs 代谢消除的 UDP-葡萄糖基转移酶（UGT）同工酶。在人肝微粒体（HLMs）孵育混合物中加入辅助因子尿苷二磷酸葡萄糖醛酸（UDPGA），检测到 CPs 的单葡糖醛酸苷。HLMs 催化的葡糖醛酸化代谢反应方程遵循米氏-门坦或底物抑制类型。利用重组酶和化学试剂抑制实验对参与 CPs 葡糖醛酸化的主要 UGT 同工酶进行表型分析。UGT1A6 可能是单氯酚异构体葡糖醛酸化的主要酶。UGT1A1、UGT1A6、UGT1A9、UGT2B4 和 UGT2B7 是代谢二氯酚和三氯酚异构体的最重要的五种 UGT 同工酶。UGT1A1 和 UGT1A3 是催化四氯酚和五氯酚异构体的最重要的 UGT 同工酶。利用大鼠肝微粒体（RLMs）、猪肝微粒体（PLMs）、狗肝微粒体（DLMs）和猴肝微粒体（MyLMs）研究了种属差异。所有这些结果都有助于阐明 CPs 的代谢消除和毒性。
