In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat
In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat
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DOI：
10.1016/j.tiv.2011.12.002
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发表时间：
2012-03-01
影响因子：
3.2
通讯作者：
Clewell, Harvey J., III
中科院分区：
文献类型：
--
作者：
Choi, Kyoungju;Joo, Hyun;Clewell, Harvey J., III
用LC-MS/MS研究了DEHP在人脑、肠、肾、肝、肺、皮肤、睾丸、大鼠肝脏和重组人和大鼠重组CYP亚细胞组分中的体外代谢。DEHP在选定的7个人体器官和大鼠肝脏的12个微体/胞质组分中能迅速降解为邻苯二甲酸单(2-乙基己基)酯(MEHP)，而在人脑和人女性皮肤的微体组分中则不能。MEHP在人和大鼠肝脏中代谢为CYP介导的氧化和脱烷基代谢物，在人肠道中的代谢速率较低。以人肝为原料，测定了邻苯二甲酸单(2-乙基-5-羟基己基)酯(5-OHMEHP)、邻苯二甲酸单乙酯(5-oxo-MEHP)、邻苯二甲酸单(2-乙基-5-羧基己基)、邻苯二甲酸单(2-羧甲基-己基)和邻苯二甲酸(PA)。人细胞色素P450亚型C9*1、细胞色素P450 C19和大鼠细胞色素P450 C6是产生5-羟基MEHP和5-OXO-MEHP代谢产物的主要CYP亚型，而只有人CYP2C9*1和2C9*2产生5-羧基MEPP。人CYP3A4和大鼠CYP3A2是MEHP通过杂原子脱烷基化产生PA的主要酶。在人肝微粒体(HLM)中，5-羟基MEHP、5-氧代MEHP、5-羧基MEPP的总归一化百分率(%TNR)分别为94%、98%和100%，由CYP3A4产生的PA的总归一化率为76%。(C)2011爱思唯尔有限公司。保留所有权利。
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. (C) 2011 Elsevier Ltd. All rights reserved.