The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, United States.
Toxicol In Vitro. 2012 Mar;26(2):315-22. doi: 10.1016/j.tiv.2011.12.002. Epub 2011 Dec 13.
In vitro metabolism of DEHP by subcellular fractions of human brain, intestine, kidney, liver, lung, skin, testis, rat liver and recombinant CYP isoforms of human and rat was investigated using LC-MS/MS. DEHP was rapidly hydrolyzed to mono(2-ethylhexyl) phthalate (MEHP) in 12 microsomal/cytosolic fractions of selected 7 human organs and rat liver but not in microsomal fractions of human brain and human female skin. MEHP was metabolized to CYP-mediated oxidative and dealkylated metabolites in human and rat liver and at a lower rate in human intestine. Measurable amounts of mono(2-ethyl-5-hydroxyhexyl) phthalate (5-OH MEHP), mono(2-ethyl-5-oxohexyl) phthalate (5-Oxo MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (5-carboxy MEPP), mono(2-carboxymethyl-hexyl) phthalate (2-carboxy MMHP) and phthalic acid (PA) were formed by human liver fractions. Human CYP2C9(∗)1, CYP2C19 and rat CYP2C6 were the major CYP isoforms producing 5-OH MEHP and 5-Oxo MEHP metabolites; however, only human CYP2C9(∗)1 and 2C9(∗)2 produced 5-carboxy MEPP from MEHP. Additionally, human CYP3A4 and rat CYP3A2 were the primary enzymes for PA production via heteroatom dealkylation of MEHP. Percent total normalized rates (%TNR) by CYP2C9(∗)1 in human liver microsomes (HLM) were 94%, 98% and 100%, respectively, for 5-OH MEHP, 5-Oxo MEHP, 5-carboxy MEPP, and 76% for PA production by CYP3A4.
采用 LC-MS/MS 法研究了邻苯二甲酸二（2-乙基己基）酯（DEHP）在人脑、肠、肾、肝、肺、皮肤、睾丸、大鼠肝的亚细胞组分和人源及大鼠源重组 CYP 同工酶中的体外代谢情况。在选定的 7 个人体器官和大鼠肝的 12 个微粒体/胞质部分中，DEHP 迅速水解为单（2-乙基己基）邻苯二甲酸酯（MEHP），但在人脑和人女性皮肤的微粒体部分中则不然。MEHP 在人肝和大鼠肝中代谢为 CYP 介导的氧化和脱烷基化代谢物，在人肠中代谢速度较低。人肝部分可形成可测数量的单（2-乙基-5-羟基己基）邻苯二甲酸酯（5-OH MEHP）、单（2-乙基-5-氧代己基）邻苯二甲酸酯（5-Oxo MEHP）、单（2-乙基-5-羧基戊基）邻苯二甲酸酯（5-羧基 MEPP）、单（2-羧基甲基-己基）邻苯二甲酸酯（2-羧基 MMHP）和邻苯二甲酸（PA）。人 CYP2C9(∗)1、CYP2C19 和大鼠 CYP2C6 是生成 5-OH MEHP 和 5-Oxo MEHP 代谢物的主要 CYP 同工酶；然而，只有人 CYP2C9(∗)1 和 2C9(∗)2 可从 MEHP 生成 5-羧基 MEPP。此外，人 CYP3A4 和大鼠 CYP3A2 是通过 MEHP 的杂原子脱烷基化生成 PA 的主要酶。人肝微粒体（HLM）中 CYP2C9(∗)1 的总归一化率（%TNR）分别为 94%、98%和 100%，用于生成 5-OH MEHP、5-Oxo MEHP、5-羧基 MEPP，而 CYP3A4 生成 PA 的%TNR 为 76%。
