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
PY - 2018/12
Y1 - 2018/12
N2 - 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.
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.
KW - BDP
KW - Human liver fractions
KW - In vitro metabolism
KW - LC-QTOF-MS
KW - Recombinant CYPs
KW - V6
UR - http://www.scopus.com/inward/record.url?scp=85053803134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053803134&partnerID=8YFLogxK
U2 - 10.1016/j.chemosphere.2018.08.142
DO - 10.1016/j.chemosphere.2018.08.142
M3 - Article
AN - SCOPUS:85053803134
SN - 0045-6535
VL - 212
SP - 1047
EP - 1057
JO - Chemosphere
JF - Chemosphere
ER -