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In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions.

Publication ,  Journal Article
Phillips, AL; Herkert, NJ; Ulrich, JC; Hartman, JH; Ruis, MT; Cooper, EM; Ferguson, PL; Stapleton, HM
Published in: Chemical research in toxicology
June 2020

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.

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Published In

Chemical research in toxicology

DOI

EISSN

1520-5010

ISSN

0893-228X

Publication Date

June 2020

Volume

33

Issue

6

Start / End Page

1428 / 1441

Related Subject Headings

  • Toxicology
  • Subcellular Fractions
  • Plasticizers
  • Organophosphates
  • Liver
  • Humans
  • Flame Retardants
  • Esters
  • Environmental Pollutants
  • Child, Preschool
 

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Phillips, A. L., Herkert, N. J., Ulrich, J. C., Hartman, J. H., Ruis, M. T., Cooper, E. M., … Stapleton, H. M. (2020). In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions. Chemical Research in Toxicology, 33(6), 1428–1441. https://doi.org/10.1021/acs.chemrestox.0c00002
Phillips, Allison L., Nicholas J. Herkert, Jake C. Ulrich, Jessica H. Hartman, Matthew T. Ruis, Ellen M. Cooper, P Lee Ferguson, and Heather M. Stapleton. “In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions.Chemical Research in Toxicology 33, no. 6 (June 2020): 1428–41. https://doi.org/10.1021/acs.chemrestox.0c00002.
Phillips AL, Herkert NJ, Ulrich JC, Hartman JH, Ruis MT, Cooper EM, et al. In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions. Chemical research in toxicology. 2020 Jun;33(6):1428–41.
Phillips, Allison L., et al. “In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions.Chemical Research in Toxicology, vol. 33, no. 6, June 2020, pp. 1428–41. Epmc, doi:10.1021/acs.chemrestox.0c00002.
Phillips AL, Herkert NJ, Ulrich JC, Hartman JH, Ruis MT, Cooper EM, Ferguson PL, Stapleton HM. In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions. Chemical research in toxicology. 2020 Jun;33(6):1428–1441.

Published In

Chemical research in toxicology

DOI

EISSN

1520-5010

ISSN

0893-228X

Publication Date

June 2020

Volume

33

Issue

6

Start / End Page

1428 / 1441

Related Subject Headings

  • Toxicology
  • Subcellular Fractions
  • Plasticizers
  • Organophosphates
  • Liver
  • Humans
  • Flame Retardants
  • Esters
  • Environmental Pollutants
  • Child, Preschool