Isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs, respectively) are plasticizers and flame retardants that are ubiquitous in indoor environments; however, no studies to date have characterized their metabolism. Using human liver subcellular S9 fractions, phase I and II in vitro metabolism of triphenyl phosphate (TPHP), 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), 2-isopropylphenyl diphenyl phosphate (2IPPDPP), and 4-isopropylphenyl diphenyl phosphate (4IPPDPP) was investigated at 1 and 10 μM doses. Parent depletion and the formation of known or suspected metabolites (e.g., likely hydrolysis or hydroxylated products), including diphenyl phosphate (DPHP), hydroxyl-triphenyl phosphate (OH-TPHP), isopropylphenyl phenyl phosphate (ip-PPP), and tert-butylphenyl phenyl phosphate (tb-PPP), were monitored and quantified via GC/MS or LC-MS/MS. tb-PPP and its conjugates were identified as the major in vitro metabolites of 4tBPDPP and accounted for 71% and 49%, respectively, of the parent molecule that was metabolized during the incubation. While the mass balance between parents and metabolites was conserved for TPHP and 4tBPDPP, approximately 20% of the initial parent mass was unaccounted for after quantifying suspected metabolites of 2IPPDPP and 4IPPDPP that had authentic standards available. Two novel ITP metabolites, mono-isopropenylphenyl diphenyl phosphate and hydroxy-isopropylphenyl diphenyl phosphate, were tentatively identified by high-resolution mass spectrometry and screened for in recently collected human urine where mono-isopropenylphenyl diphenyl phosphate was detected in one of nine samples analyzed. This study provides insight into the biological fate of ITP and TBPP isomers in human tissues and is useful in identifying appropriate biomarkers of exposure to monitor, particularly in support of epidemiological studies.

中文翻译：

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使用人肝亚细胞级分的异丙基化和叔丁基化磷酸三芳基酯的体外代谢。

异丙基和叔丁基化三芳基磷酸酯（分别为ITP和TBPP）是在室内环境中普遍存在的增塑剂和阻燃剂。然而，迄今为止，尚无研究对其代谢进行表征。使用人肝S9亚细胞级分，一期和二期体外（TPHP）磷酸三苯酯的代谢，4-叔以1和10μM的剂量研究了丁基丁基苯基二苯基磷酸酯（4tBPDPP），2-异丙基苯基二苯基磷酸酯（2IPPDPP）和4-异丙基苯基二苯基磷酸酯（4IPPDPP）。母体耗竭并形成已知或可疑的代谢物（例如可能的水解或羟化产物），包括磷酸二苯酯（DPHP），羟基三苯磷酸酯（OH-TPHP），异丙基苯基磷酸苯酯（ip-PPP）和叔丁基苯基通过GC / MS或LC-MS / MS对磷酸苯酯（tb-PPP）进行监测和定量。tb-PPP及其结合物被鉴定为主要体外4tBPDPP的代谢产物分别占孵育过程中代谢的亲本分子的71％和49％。尽管保留了TPHP和4tBPDPP母体和代谢物之间的质量平衡，但在对具有可靠标准品的2IPPDPP和4IPPDPP的可疑代谢物进行定量后，约占初始母体质量的20％仍未确定。通过高分辨率质谱法初步鉴定了两种新型的ITP代谢产物磷酸单异丙烯基苯基二苯酯和羟基异丙基苯基二苯基磷酸酯，并在最近收集的人类尿液中进行了筛查，在其中分析的9个样品之一中检测到磷酸单异丙烯基苯基二苯基酯。