title: Human hydroxylated metabolites of BDE-47 and BDE-99 are glucuronidated and sulfated in vitro.
abstract: Polybrominated diphenyl ethers (PBDEs) were used worldwide as additive flame retardants and are classified as persistent, bioaccumulable and toxic environmental pollutants. In humans, the hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) formed in vitro have also been detected in vivo. To further characterize the metabolism of BDE-47 and BDE-99 and to identify candidate markers for monitoring the human exposure to PBDEs using non-invasive approaches, glucuronidation and sulfation of hydroxylated metabolites of BDE-47 and BDE-99 were investigated using human liver microsomes and cytoplasm, respectively. The formed Phase II metabolites were analyzed by liquid chromatography-tandem mass spectrometry using a novel approach to develop analytical methods in absence of authentic standards. All available standards for hydroxylated metabolites of BDE-47 and BDE-99 were glucuronidated and sulfated, showing that glucuronidation and sulfation are part of the metabolism pathway of BDE-47 and BDE-99 in vitro. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-47 were (a) 2,4-DBP-Gluc and 5-Gluc-BDE-47, and (b) 2'-Sulf-BDE-28, 4-Sulf-BDE-42 and 3-Sulf-BDE-47, respectively. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-99 were (a) 2,4,5-TBP-Gluc and 6'-Gluc-BDE-99, and (b) 3'-Sulf-BDE-99 and 5'-Sulf-BDE-99, respectively. Apparent Km values associated with the formation of sulfated metabolites of BDE-47 and BDE-99 were ten times lower than those of the corresponding glucuronidated metabolites, suggesting that sulfated rather than glucuronidated metabolites of OH-PBDEs might be used as markers of human exposure to PBDEs using a non-invasive approach based on urine sample collection.
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium. Electronic address: claudio.erratico@uantwerpen.be.
authors.forename: Claudio
authors.initials: C
authors.lastname: Erratico
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium; Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 90 Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ryden
authors.affiliation: Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 90 Stockholm, Sweden.
authors.forename: Goran
authors.initials: G
authors.lastname: Marsh
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
authors.forename: Walid
authors.initials: W
authors.lastname: Maho
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covaci
mesh_terms: D015415:Biomarkers; D002853:Chromatography, Liquid; D003593:Cytoplasm / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D013431:Sulfates / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: C477694:2,2',4,4',5-brominated diphenyl ether; D015415:Biomarkers; D020719:Glucuronides; D055768:Halogenated Diphenyl Ethers; D013431:Sulfates; C511295:2,2',4,4'-tetrabromodiphenyl ether
keywords: BDE-47; BDE-99; Glucuronidated and sulfated metabolites; In vitro; SULTs; UGTs