Metabolic Mechanism of Aryl Phosphorus Flame Retardants by Cytochromes P450: A Combined Experimental and Computational Study on Triphenyl Phosphate
2018
Zhang, Quan | Ji, Shujing | Chai, Lihong | Yang, Fangxing | Zhao, Meirong | Liu, Weiping | Schüürmann, Gerrit | Li, Ji
Understanding metabolic mechanisms is critical and remains a difficult task in the risk assessment of emerging pollutants. Triphenyl phosphate (TPHP), a widely used aryl phosphorus flame retardant (aryl-PFR), has been frequently detected in the environment, and its major metabolite was considered as diphenyl phosphate (DPHP). However, knowledge of the mechanism for TPHP leading to DPHP and other metabolites is lacking. Our in vitro study shows that TPHP is metabolized into its diester metabolite DPHP and mono- and dihydroxylated metabolites by cytochromes P450 (CYP) in human liver microsomes, while CYP1A2 and CYP2E1 isoforms are mainly involved in such processes. Molecular docking gives the conformation for TPHP binding with the active species Compound I (an iron IV-oxo heme cation radical) in specific CYP isoforms, showing that the aromatic ring of TPHP is likely to undergo metabolism. Quantum chemical calculations have shown that the dominant reaction channel is the O-addition of Compound I onto the aromatic ring of TPHP, followed by a hydrogen-shuttle mechanism leading to ortho-hydroxy-TPHP as the main monohydroxylated metabolite; the subsequent H-abstraction–OH-rebound reaction acting on ortho-hydroxy-TPHP yields the meta- and ipso-position quinol intermediates, while the former of which can be metabolized into dihydroxy-TPHP by fast protonation, and the latter species needs to go through type-I ipso-substitution and fast protonation to be evolved into DPHP. We envision that the identified mechanisms may give inspiration for studying the metabolism of several other aryl-PFRs by CYP.
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