Van den Eede Nele, Tomy Gregg, Tao Fang, Halldorson Thor, Harrad Stuart, Neels Hugo, Covaci Adrian
Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium.
Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada.
Chemosphere. 2016 Feb;144:1299-305. doi: 10.1016/j.chemosphere.2015.09.049. Epub 2015 Oct 23.
Tris(1-chloro-2-propyl) phosphate (TCIPP) is an emerging contaminant which is ubiquitous in the indoor and outdoor environment. Moreover, its presence in human body fluids and biota has been evidenced. Since no quantitative data exist on the biotransformation or stability of TCIPP in the human body, we performed an in vitro incubation of TCIPP with human liver microsomes (HLM) and human serum (HS). Two metabolites, namely bis(2-chloro-isopropyl) phosphate (BCIPP) and bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), were quantified in a kinetic study using HLM or HS (only BCIPP, the hydrolysis product) and LC-MS. The Michaelis-Menten model fitted best the NADPH-dependent formation of BCIPHIPP and BCIPP in HLM, with respective V(MAX) of 154 ± 4 and 1470 ± 110 pmol/min/mg protein and respective apparent K(m) of 80.2 ± 4.4 and 96.1 ± 14.5 μM. Hydrolases, which are naturally present in HLM, were also involved in the production of BCIPP. A HS paraoxonase assay could not detect any BCIPP formation above 38.6 ± 10.8 pmol/min/μL serum. Our data indicate that BCIPP is the major metabolite of TCIPP formed in the liver. To our knowledge, this is the first quantitative assessment of the stability of TCIPP in tissues of humans or any other species. Further research is needed to confirm whether these biotransformation reactions are associated with a decrease or increase in toxicity.
磷酸三（1-氯-2-丙基）酯（TCIPP）是一种新兴污染物，在室内和室外环境中普遍存在。此外，其在人体体液和生物群中的存在也已得到证实。由于目前尚无关于TCIPP在人体内生物转化或稳定性的定量数据，我们进行了TCIPP与人肝微粒体（HLM）和人血清（HS）的体外孵育实验。在一项动力学研究中，使用HLM或HS（仅水解产物BCIPP）和液相色谱-质谱联用技术对两种代谢产物，即磷酸双（2-氯异丙基）酯（BCIPP）和磷酸双（1-氯-2-丙基）1-羟基-2-丙酯（BCIPHIPP）进行了定量分析。米氏模型最适合描述HLM中BCIPHIPP和BCIPP的NADPH依赖性形成过程，其V(MAX)分别为154±4和1470±110 pmol/min/mg蛋白，表观K(m)分别为80.2±4.4和96.1±14.5 μM。HLM中天然存在的水解酶也参与了BCIPP的生成。HS对氧磷酶测定未检测到高于38.6±10.8 pmol/min/μL血清的BCIPP形成。我们的数据表明，BCIPP是肝脏中形成的TCIPP的主要代谢产物。据我们所知，这是首次对TCIPP在人类或任何其他物种组织中的稳定性进行定量评估。需要进一步研究以确认这些生物转化反应是否与毒性降低或增加有关。
