title: Stereoselective Metabolism of α-, β-, and γ-Hexabromocyclododecanes (HBCDs) by Human Liver Microsomes and CYP3A4.
abstract: This is the first study investigating the in vitro metabolism of α-, β-, and γ-hexabromocyclododecane (HBCD) stereoisomers in humans and providing semiquantitative metabolism data. Human liver microsomes were incubated with individual racemic mixtures and with individual stereoisomers of α-, β-, and γ-HBCDs, the hydroxylated metabolites formed were analyzed by liquid chromatography-tandem mass spectrometry, and the value of the intrinsic in vitro clearance (Clint,vitro) was calculated. Several mono- and dihydroxylated metabolites of α-, β-, and γ-HBCDs were formed, with mono-OH-HBCDs being the major metabolites. No stereoisomerization of any of the six α-, β-, and γ-HBCD isomers catalyzed by cytochrome P450 (CYP) enzymes occurred. The value of Clint,vitro of α-HBCDs was significantly lower than that of β-HBCDs, which, in turn, was significantly lower than that of γ-HBCDs (p < 0.05). Such differences were explained by the significantly lower values of Clint,vitro of each α-HBCD stereoisomer than those of the β- and γ-HBCD stereoisomers. In addition, significantly lower values of Clint,vitro of the (-) over the (+)α- and β-HBCD stereoisomers, but not γ-HBCDs, were obtained. Our data offer a possible explanation of the enrichment of α-HBCDs over β- and γ-HBCDs on the one hand and, on the other hand, of (-)α-HBCDs over (+)α-HBCDs previously reported in human samples. It also offers information about the mechanism resulting in such enrichments, the stereoisomer-selective metabolism of α-, β-, and γ-HBCDs catalyzed by CYPs with the lack of stereoisomerization.
authors.affiliation: Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Claudio
authors.initials: C
authors.lastname: Erratico
authors.affiliation: Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Wilrijk, Belgium.|Guangzhou Institute of Geochemistry, Chinese Academy of Sciences , Guangzhou 510640, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: van den Eede
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg R3T 2N2, Canada.
authors.forename: Gregg
authors.initials: G
authors.lastname: Tomy
authors.affiliation: Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covaci
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A