title: In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat.
abstract: 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.
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, United States. kchoi@thehamner.org
authors.forename: Kyoungju
authors.initials: K
authors.lastname: Choi
authors.forename: Hyun
authors.initials: H
authors.lastname: Joo
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Campbell
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Clewell
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
mesh_terms: D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010968:Plasticizers / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013737:Testis / Q000378:metabolism
chemical_list: D010968:Plasticizers; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate