Stereoselective Metabolism of α-, β-, and γ-Hexabromocyclododecanes (HBCDs) by Human Liver Microsomes and CYP3A4

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• 作者：Claudio Erratico ; Xiaobo Zheng ; Nele van den Eede ; Gregg Tomy ; Adrian Covaci
• 刊名：Environmental Science & Technology
• 出版年：2016
• 出版时间：August 2, 2016
• 年：2016
• 卷：50
• 期：15
• 页码：8263-8273
• 全文大小：638K
• 年卷期：0
• ISSN：1520-5851

文摘

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 (Cl_int,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 Cl_int,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 Cl_int,vitro of each α-HBCD stereoisomer than those of the β- and γ-HBCD stereoisomers. In addition, significantly lower values of Cl_int,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.