In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat

被引：75
作者：
Choi, Kyoungju [1 ]
Joo, Hyun [1 ]
Campbell, Jerry L., Jr. [1 ]
Clewell, Rebecca A. [1 ]
Andersen, Melvin E. [1 ]
Clewell, Harvey J., III [1 ]
机构：
[1] Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA
来源：
TOXICOLOGY IN VITRO | 2012年 / 26卷 / 02期
关键词：
DEHP; In vitro metabolism; Human tissues; Rat tissues; Cytochrome P450; LC-MS/MS; HUMAN LIVER-MICROSOMES; DI-(2-ETHYLHEXYL) PHTHALATE; SPECIES-DIFFERENCES; FETAL TESTIS; HUMAN SPERM; INHIBITION; HYDROLYSIS; ABSORPTION; EXPOSURE; ISOFORMS;
D O I：
10.1016/j.tiv.2011.12.002
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
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.
引用
收藏
页码：315 / 322
页数：8
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