School of Public Health, North Sichuan Medical College, Nanchong 637000, China.
Chongqing Qijiang District for Disease Control and Prevention, Chongqing 401420, China.
Toxicol Appl Pharmacol. 2024 Jan;482:116785. doi: 10.1016/j.taap.2023.116785. Epub 2023 Dec 7.
Phthalate esters (PAEs), accompanied by phthalate monoesters as hydrolysis metabolites in humans, have been widely used as plasticizers and exhibited disruptive effects on the endocrine and metabolic systems. The present study aims to investigate the inhibition behavior of PAEs and phthalate monoesters on the activity of the important hydrolytic enzymes, carboxylesterases (CESs), to elucidate the toxicity mechanism from a new perspective. The results showed significant inhibition on CES1 and CES2 by most PAEs, but not by phthalate monoesters, above which the activity of CES1 was strongly inhibited by DCHP, DEHP, DiOP, DiPP, DNP, DPP and BBZP, with inhibition ratios exceeding 80%. Kinetic analyses and in vitro-in vivo extrapolation were conducted, revealing that PAEs have the potential to disrupt the metabolism of endogenous substances catalyzed by CES1 in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of PAEs towards CES1. These findings will be beneficial for understanding the adverse effect of PAEs and phthalate monoesters.
邻苯二甲酸酯（PAEs）及其在人体内的水解代谢产物邻苯二甲酸单酯，被广泛用作增塑剂，并对内分泌和代谢系统表现出破坏作用。本研究旨在探讨 PAEs 和邻苯二甲酸单酯对重要水解酶羧酸酯酶（CESs）活性的抑制行为，从新的角度阐明其毒性机制。结果表明，大多数 PAEs 对 CES1 和 CES2 具有显著的抑制作用，但邻苯二甲酸单酯则没有，其中 DCHP、DEHP、DiOP、DiPP、DNP、DPP 和 BBZP 强烈抑制 CES1 的活性，抑制率超过 80%。进行了动力学分析和体外-体内外推，结果表明 PAEs 有可能在体内破坏 CES1 催化的内源性物质的代谢。分子对接结果表明，酯键形成的氢键和疏水接触有助于 PAEs 与 CES1 的相互作用。这些发现将有助于理解 PAEs 和邻苯二甲酸单酯的不良影响。
