Mass spectrometric identification of in vitro-generated metabolites of two emerging organophosphate flame retardants: V6 and BDP

Andreia Alves, Claudio Erratico, Luisa Lucattini, Matthias Cuykx, Ana Ballesteros-Gómez, Pim E.G. Leonards, Stefan Voorspoels, Adrian Covaci

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The aim of the present study was to investigate the in vitro metabolism of two emerging organophosphate flame retardants, namely tetrekis(2-chlorethyl)dichloroisopentyldiphosphate (V6) and bisphenol-A bis-diphenyl phosphate (BDP) in human liver microsomes (HLMs), HLM S9 fractions and in human serum. In particular, the role of cytochrome P450 (CYPs) enzymes and/or paraoxonases (PONs) in the formation of V6 and BDP phase I metabolites was studied. Mono-, di-hydroxylated and hydrolytic phase I metabolites of V6 were mainly formed by CYPs in HLMs, while hydrolytic and O-dealkylated phase I metabolites of BDP were generated by PONs mainly in serum experiments. Limited number of glucuronidated and sulfated phase II metabolites were also identified for the two chemicals. The activity of seven recombinant CYPs (rCYPs) including rCYP1A2, rCYP2B6, rCYP2C9, rCYP2C19, rCYP2D6, rCYP2E1 and rCYP3A4 in the in vitro phase I metabolism of V6 and BDP was investigated. The formation of V6 metabolites was catalyzed by several enzymes, especially rCYP1A2 that was responsible for the exclusive formation of two metabolites, one primary (M1) and its secondary metabolite (M9). For BDP, only one phase I metabolite (MM1) was catalyzed by the seven rCYPs. Collectively, these results indicate that CYPs have a predominant role in the metabolism of V6, while PONs have a predominant role in BDP in vitro metabolism. These results are a starting point for future studies involving the study of the toxicity, bioaccumulation and in vivo biomonitoring of V6 and BDP.

Original languageEnglish
Pages (from-to)1047-1057
Number of pages11
JournalChemosphere
Volume212
Early online date3 Sep 2018
DOIs
Publication statusPublished - Dec 2018

Fingerprint

Flame Retardants
Organophosphates
organophosphate
Flame retardants
Metabolites
metabolite
Phosphates
phosphate
Cytochrome P-450 Enzyme System
cytochrome
Metabolism
Liver Microsomes
metabolism
Liver
serum
enzyme
Environmental Monitoring
secondary metabolite
Bioaccumulation
biomonitoring

Keywords

  • BDP
  • Human liver fractions
  • In vitro metabolism
  • LC-QTOF-MS
  • Recombinant CYPs
  • V6

Cite this

Alves, Andreia ; Erratico, Claudio ; Lucattini, Luisa ; Cuykx, Matthias ; Ballesteros-Gómez, Ana ; Leonards, Pim E.G. ; Voorspoels, Stefan ; Covaci, Adrian. / Mass spectrometric identification of in vitro-generated metabolites of two emerging organophosphate flame retardants : V6 and BDP. In: Chemosphere. 2018 ; Vol. 212. pp. 1047-1057.
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Mass spectrometric identification of in vitro-generated metabolites of two emerging organophosphate flame retardants : V6 and BDP. / Alves, Andreia; Erratico, Claudio; Lucattini, Luisa; Cuykx, Matthias; Ballesteros-Gómez, Ana; Leonards, Pim E.G.; Voorspoels, Stefan; Covaci, Adrian.

In: Chemosphere, Vol. 212, 12.2018, p. 1047-1057.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Mass spectrometric identification of in vitro-generated metabolites of two emerging organophosphate flame retardants

T2 - V6 and BDP

AU - Alves, Andreia

AU - Erratico, Claudio

AU - Lucattini, Luisa

AU - Cuykx, Matthias

AU - Ballesteros-Gómez, Ana

AU - Leonards, Pim E.G.

AU - Voorspoels, Stefan

AU - Covaci, Adrian

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AB - The aim of the present study was to investigate the in vitro metabolism of two emerging organophosphate flame retardants, namely tetrekis(2-chlorethyl)dichloroisopentyldiphosphate (V6) and bisphenol-A bis-diphenyl phosphate (BDP) in human liver microsomes (HLMs), HLM S9 fractions and in human serum. In particular, the role of cytochrome P450 (CYPs) enzymes and/or paraoxonases (PONs) in the formation of V6 and BDP phase I metabolites was studied. Mono-, di-hydroxylated and hydrolytic phase I metabolites of V6 were mainly formed by CYPs in HLMs, while hydrolytic and O-dealkylated phase I metabolites of BDP were generated by PONs mainly in serum experiments. Limited number of glucuronidated and sulfated phase II metabolites were also identified for the two chemicals. The activity of seven recombinant CYPs (rCYPs) including rCYP1A2, rCYP2B6, rCYP2C9, rCYP2C19, rCYP2D6, rCYP2E1 and rCYP3A4 in the in vitro phase I metabolism of V6 and BDP was investigated. The formation of V6 metabolites was catalyzed by several enzymes, especially rCYP1A2 that was responsible for the exclusive formation of two metabolites, one primary (M1) and its secondary metabolite (M9). For BDP, only one phase I metabolite (MM1) was catalyzed by the seven rCYPs. Collectively, these results indicate that CYPs have a predominant role in the metabolism of V6, while PONs have a predominant role in BDP in vitro metabolism. These results are a starting point for future studies involving the study of the toxicity, bioaccumulation and in vivo biomonitoring of V6 and BDP.

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