New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP
New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP
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DOI：
10.1007/s00204-004-0642-4
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发表时间：
2005-07-01
影响因子：
6.1
通讯作者：
Angerer, J
中科院分区：
文献类型：
--
作者：
Koch, HM;Bolt, HM;Angerer, J
对一名男性志愿者口服0.35 mg（4.7 μ g/kg）、2.15 mg（28.7 μ g/kg）和48.5 mg（650 μ g/kg）三种剂量的D4环标记DEHP后，研究了邻苯二甲酸二（2-乙基己基）酯（DEHP）在人体内的代谢。两种新代谢产物，mono邻苯二甲酸2-乙基-5-羧基戊酯（5cx-MEPP）和单[2-邻苯二甲酸（羧甲基）己酯除了先前分析的三种代谢物外，在高剂量情况下，还在尿液中监测44小时，在血清中监测8小时：邻苯二甲酸单（2-乙基-5-羟己基）酯（5 OH-MEHP）、邻苯二甲酸单（2-乙基-5-氧代己基）酯（5 oxo-MEHP）和邻苯二甲酸单（2-乙基己基）酯（MEHP）。对于中剂量和低剂量病例，分析了24小时尿样。给药后12小时内，5 OH-MEHP是主要的尿液代谢物，12小时后为5cx-MEPP，24小时后为2cx-MMHP。5cx-MEHP和2cx-MMHP的消除半衰期在15 - 24 h之间。24小时后，67.0%（范围：65.8-70.5%）的DEHP剂量经尿液排泄，包括5 OH-MEHP（23.3%）、5cx-MEPP（18.5%）、5 oxo-MEHP（15.0%）、MEHP（5.9%）和2cx-MMHP（4.2%）。在第二天排出额外3.8%的DEHP剂量，包括2cx-MMHP（1.6%）、5cx-MEPP（1.2%）、5 OH-MEHP（0.6%）和5 oxo-MEHP（0.4%）。两天后，约75%的DEHP剂量通过尿液排出。因此，与先前的研究相反，大部分口服DEHP被全身吸收并经尿液排泄。未观察到代谢和排泄的剂量依赖性。与任何其他参数（如尿液或血液中的MEHP）相比，DEHP的次级代谢产物是上级生物监测标志物。尿液中的5 OH-MEHP和5 oxo-MEHP反映短期暴露，5cx-MEHP和2cx-MMHP反映长期暴露。所有次级代谢产物均不易受污染。此外，有强烈的迹象表明，二次氧化DEHP代谢物-而不是DEHP或MEHP-是最终的发育毒物。
The metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans was studied after three doses of 0.35 mg (4.7 mu g/kg), 2.15 mg (28.7 mu g/kg) and 48.5 mg (650 mu g/kg) of D4-ring-labelled DEHP were administered orally to a male volunteer. Two new metabolites, mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) were monitored for 44 h in urine and for 8 h in serum for the high-dose case, in addition to the three metabolites previously analysed: mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP). For the medium- and low-dose cases, 24 h urine samples were analysed. Up to 12 h after the dose, 5OH-MEHP was the major urinary metabolite, after 12 h it was 5cx-MEPP, and after 24 h it was 2cx-MMHP. The elimination half-lives of 5cx-MEHP and 2cx-MMHP were between 15 and 24 h. After 24 h 67.0% (range: 65.8-70.5%) of the DEHP dose was excreted in urine, comprising 5OH-MEHP (23.3%), 5cx-MEPP (18.5%), 5oxo-MEHP (15.0%), MEHP (5.9%) and 2cx-MMHP (4.2%). An additional 3.8% of the DEHP dose was excreted on the second day, comprising 2cx-MMHP (1.6%), 5cx-MEPP (1.2%), 5OH-MEHP (0.6%) and 5oxo-MEHP (0.4%). In total about 75% of the administered DEHP dose was excreted in urine after two days. Therefore, in contrast to previous studies, most of the orally administered DEHP is systemically absorbed and excreted in urine. No dose dependency in metabolism and excretion was observed. The secondary metabolites of DEHP are superior biomonitoring markers compared to any other parameters, such as MEHP in urine or blood. 5OH-MEHP and 5oxo-MEHP in urine reflect short-term and 5cx-MEHP and 2cx-MMHP long-term exposure. All secondary metabolites are unsusceptible to contamination. Furthermore, there are strong hints that the secondary oxidised DEHP metabolites-not DEHP or MEHP-are the ultimate developmental toxicants.