In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions
Autor: | Jessica H. Hartman, P. Lee Ferguson, Ellen M. Cooper, Jake C. Ulrich, Matthew T. Ruis, Nicholas J Herkert, Allison L. Phillips, Heather M. Stapleton |
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Rok vydání: | 2020 |
Předmět: |
0303 health sciences
Chromatography General Medicine Metabolism Urine 010501 environmental sciences Toxicology Phosphate 01 natural sciences In vitro 03 medical and health sciences chemistry.chemical_compound Hydrolysis chemistry Biotransformation DPHP 030304 developmental biology 0105 earth and related environmental sciences Triphenyl phosphate |
Zdroj: | Chemical Research in Toxicology. 33:1428-1441 |
ISSN: | 1520-5010 0893-228X |
Popis: | 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. |
Databáze: | OpenAIRE |
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