In vitro biotransformation of tris(1,3-dichloro-2-propyl) phosphate and triphenyl phosphate by mouse liver microsomes: Kinetics and key CYP isoforms

Abstract As the result of the phase-out on polybrominated diphenyl ethers, organophosphate flame retardants (OPFRs) were widely used as substitutes in the world. Previous studies found that OPFRs were frequently detected in environmental, biological, and human samples. Considering their adverse effects, the absorption, bioaccumulation, metabolism and internal exposure processes of OPFRs attracted more attentions recently, especially for aryl-OPFR and Cl-OPFRs. In the present study, the biotransformation, metabolic kinetics and related CYP450 isoforms of typical Cl-OPFR (tris(1,3-dichloro-2-propyl) phosphate: TDCPP) and aryl-OPFR (triphenyl phosphate: TPhP) were studied in vitro by mouse liver microsomes. Metabolomic analysis revealed that TDCPP may be easier to bio-accumulate in organisms than TPhP, which can be explained by their metabolic rates and half-life values (TDCPP: t1/2 = 1.8083 h; TPhP: t1/2 = 0.1531 h). CYP2E1, CYP2D6, CYP1A2 and CYP2C19 were suggested to be the specific enzymes for the biotransformation of TDCPP via associated inhibition assay. CYP2E1 was the primary CYP450 isoform of metabolism in vitro for TPhP. These findings may provide new insights for the potential mechanism of hepatotoxicity in mammals induced by OPFRs and the detoxification process of OPFRs in hepatocytes.