Oxidative metabolism of BDE-47, BDE-99, and HBCDs by cat liver microsomes: Implications of cats as sentinel species to monitor human exposure to environmental pollutants

Abstract

The in vitro oxidative metabolism of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99), and individual α-, β- and γ-hexabromocyclododecane (HBCD) isomers catalyzed by cytochrome P450 (CYP) enzymes was screened using cat liver microsomes (CLMs). Six hydroxylated metabolites, namely 4-hydroxy-2,2′,3,4′-tetrabromodiphenyl ether (4-OH-BDE-42), 3-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (3-OH-BDE-47), 5-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (5-OH-BDE-47), 6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE-47), 4′-hydroxy-2,2′,4,5′- tetrabromodiphenyl ether (4′-OH-BDE-49), and 2′-hydroxy-2,3′,4,4′-tetrabromodiphenyl ether (2′-OH-BDE-66), were identified and quantified after incubation of BDE-47. A di-OH-tetra-BDE was also found as metabolite of BDE-47 with CLMs. 5-OH-BDE-47 was the major metabolite formed. Five hydroxylated metabolites (3′-hydroxy-2,2′,4,4′,5-pentabromodiphenyl ether (3′-OH-BDE-99), 5′-hydroxy-2,2′,4,4′,5-pentabromodiphenyl ether (5′-OH-BDE-99), 6-hydroxy-2,2′,4,4′,5-pentabromodiphenyl ether (6-OH-BDE-99), 6′-hydroxy-2,2′,4,4′,5-pentabromodiphenyl ether (6′-OH-BDE-99), and 4′-hydroxy-2,2′,4,5,5′-pentabromodiphenyl ether (4′-OH-BDE-101) were formed from BDE-99 incubated with CLMs. Concentrations of BDE-99 metabolites were lower than those of BDE-47. Four or more mono-hydroxylated HBCD (OH-HBCDs), four or more di-hydroxylated HBCD (di-OH-HBCDs), five or more mono-hydroxylated pentabromocyclododecanes (OH-PBCDs), and five or more di-hydroxylated pentabromocyclododecenes (di-OH-PBCDs) were detected after incubation of α-, β-, or γ-HBCD with CLMs. No diastereoisomeric or enantiomeric enzymatic isomerisation was observed incubating α-, β- or γ-HBCD with CLMs. Collectively, our data suggest that (i) BDE-47 is metabolized at a faster rate than BDE-99 by CLMs, (ii) OH-HBCDs are the major hydroxylated metabolites of α-, β- and γ-HBCD produced by CLMs, and (iii) the oxidative metabolism of BDE-47 and BDE-99 is different by cat and human liver microsomes. This suggests that cats are not a suitable sentinel to represent internal exposure of PBDEs for humans, but is likely a promising sentinel for internal HBCDs exposure for humans.