In Vitro Metabolism of Isopropylatedand tert-Butylated Triarylphosphate Esters UsingHuman Liver Subcellular Fractions Article Swipe
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· 2020
· Open Access
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· DOI: https://doi.org/10.1021/acs.chemrestox.0c00002.s001
· OA: W3011765737
Isopropylated\nand <i>tert</i>-butylated triarylphosphate\nesters (ITPs and TBPPs, respectively) are plasticizers and flame retardants\nthat are ubiquitous in indoor environments; however, no studies to\ndate have characterized their metabolism. Using human liver subcellular\nS9 fractions, phase I and II <i>in vitro</i> metabolism\nof triphenyl phosphate (TPHP), 4-<i>tert</i>-butylphenyl\ndiphenyl phosphate (4tBPDPP), 2-isopropylphenyl diphenyl phosphate\n(2IPPDPP), and 4-isopropylphenyl diphenyl phosphate (4IPPDPP) was\ninvestigated at 1 and 10 μM doses. Parent depletion and the\nformation of known or suspected metabolites (e.g., likely hydrolysis\nor hydroxylated products), including diphenyl phosphate (DPHP), hydroxyl-triphenyl\nphosphate (OH-TPHP), isopropylphenyl phenyl phosphate (ip-PPP), and <i>tert</i>-butylphenyl phenyl phosphate (tb-PPP), were monitored\nand quantified via GC/MS or LC-MS/MS. tb-PPP and its conjugates were\nidentified as the major <i>in vitro</i> metabolites of 4tBPDPP\nand accounted for 71% and 49%, respectively, of the parent molecule\nthat was metabolized during the incubation. While the mass balance\nbetween parents and metabolites was conserved for TPHP and 4tBPDPP,\napproximately 20% of the initial parent mass was unaccounted for after\nquantifying suspected metabolites of 2IPPDPP and 4IPPDPP that had\nauthentic standards available. Two novel ITP metabolites, mono-isopropenylphenyl\ndiphenyl phosphate and hydroxy-isopropylphenyl diphenyl phosphate,\nwere tentatively identified by high-resolution mass spectrometry and\nscreened for in recently collected human urine where mono-isopropenylphenyl\ndiphenyl phosphate was detected in one of nine samples analyzed. This\nstudy provides insight into the biological fate of ITP and TBPP isomers\nin human tissues and is useful in identifying appropriate biomarkers\nof exposure to monitor, particularly in support of epidemiological\nstudies.
