title: 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.
authors.affiliation: Key Laboratory of Soil Environment and Waste Reuse in Agriculture of Guangdong Higher Education Institutions, College of Resources and Environment, South China Agricultural University, Guangzhou 510642, China; Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry and Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Chinese Academy of Sciences, Guangzhou 510640, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Claudio
authors.initials: C
authors.lastname: Erratico
authors.affiliation: State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry and Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Chinese Academy of Sciences, Guangzhou 510640, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry and Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Chinese Academy of Sciences, Guangzhou 510640, China.
authors.forename: Bixian
authors.initials: B
authors.lastname: Mai
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium. Electronic address: adrian.covaci@uantwerpen.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covaci
mesh_terms: D000818:Animals; D002415:Cats; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004784:Environmental Monitoring / Q000379:methods; D004785:Environmental Pollutants / Q000378:metabolism*; D055768:Halogenated Diphenyl Ethers / Q000378:metabolism*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000378:metabolism*; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism*
chemical_list: C477694:2,2',4,4',5-brominated diphenyl ether; D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated; C511295:2,2',4,4'-tetrabromodiphenyl ether; C089796:hexabromocyclododecane; D003577:Cytochrome P-450 Enzyme System
keywords: Cat liver microsomes; Cytochrome P450; Hexabromocyclododecanes; Metabolism; Polybrominated diphenyl ethers