Biotransformation of BDE-47 to potentially toxic metabolites is predominantly mediated by human CYP2B6.
Biotransformation of BDE-47 to potentially toxic metabolites is predominantly mediated by human CYP2B6.
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DOI：
10.1289/ehp.1205446
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发表时间：
2013-04
影响因子：
10.4
通讯作者：
Olson JR
中科院分区：
文献类型：
--
作者：
Feo ML;Gross MS;McGarrigle BP;Eljarrat E;Barceló D;Aga DS;Olson JR
背景：先前的研究表明，细胞色素p450 （CYPs）参与人体多溴联苯醚（PBDE）阻燃剂的代谢，导致羟基化PBDEs （OH-PBDEs）的形成，其毒性可能比母体PBDEs更大。然而，负责形成oh -多溴二苯醚的特定酶是未知的。目的：研究2,2´，4,4´-四溴联苯醚（BDE-47）在人肝微粒体（HLM）和重组人CYP的体外代谢，并鉴定参与BDE-47氧化代谢的CYP。方法：重组人CYPs （CYP1A1、1A2、1B1、2A6、2B6、2C8、2C9、2C19、2D6、2E1、3A4）用BDE-47（20µM）孵育，采用气相色谱-串联质谱（GC-MS/MS）测定代谢产物并进行表征。为了进行动力学研究，CYP2B6和合并的人肝微粒体（HLMs）用BDE-47（0-60µM）孵育。结果：CYP2B6是主要的CYP，能够形成6种oh - bde，包括3-OH-BDE-47, 5-OH-BDE-47, 6-OH-BDE-47, 4- oh - bde -42, 4 ' -OH-BDE-49，以及初步鉴定为2 ' -OH-BDE-66的代谢物。在全扫描GC-MS分析的基础上，我们假设形成了另外两种代谢物：二氧四溴二苯醚和二氧四溴化二恶英。在CYP2B6和汇总HLMs代谢BDE-47的动力学研究中，我们发现Km值分别在3.8 ~ 6.4µM和7.0 ~ 11.4µM之间，表明对OH-BDEs的形成具有高亲和力。结论：我们的研究结果支持CYP2B6在BDE-47代谢潜在毒性代谢物（包括假设的二羟基四溴化二恶英代谢物）中的主要作用。这些结果将有助于未来的流行病学研究，调查多溴二苯醚及其代谢物产生神经行为/神经发育障碍的可能性。
Background: Previous studies have indicated that cytochrome P450s (CYPs) are involved in the metabolism of polybrominated diphenyl ether (PBDE) flame retardants in humans, resulting in the formation of hydroxylated PBDEs (OH-PBDEs) that are potentially more toxic than the parent PBDEs. However, the specific enzymes responsible for the formation of OH-PBDEs are unknown. Objectives: The purposes of this study were to characterize the in vitro metabolism of 2,2´,4,4´-tetrabromodiphenyl ether (BDE-47) by human liver microsomes (HLM) and recombinant human CYPs, and to identify the CYP(s) that are active in the oxidative metabolism of BDE-47. Methods: Recombinant human CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) were incubated with BDE-47 (20 µM), and the metabolites were measured and characterized using gas chromatography with tandem mass spectrometry (GC-MS/MS). For kinetic studies, CYP2B6 and pooled human liver microsomes (HLMs) were incubated with BDE-47 (0–60 µM). Results: CYP2B6 was the predominant CYP capable of forming six OH-BDEs, including 3-OH-BDE-47, 5-OH-BDE-47, 6-OH-BDE-47, 4-OH-BDE-42, 4´-OH-BDE-49, and a metabolite tentatively identified as 2´-OH-BDE-66. On the basis of full-scan GC-MS analysis, we hypothesized the formation of two other metabolites: di-OH-tetra-BDE and di-OH-tetrabrominated dioxin. In kinetic studies of BDE-47 metabolism by CYP2B6 and pooled HLMs, we found Km values ranging from 3.8 to 6.4 µM and 7.0 to 11.4 µM, respectively, indicating the high affinity toward the formation of OH-BDEs. Conclusion: Our findings support a predominant role of CYP2B6 in the metabolism of BDE-47 to potentially toxic metabolites, including a hypothesized di-OH-tetrabrominated dioxin metabolite. These results will assist future epidemiological studies investigating the potential of PBDEs and their metabolites to produce neurobehavioral/neurodevelopmental disorders.
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影响因子：
10.4
作者：
Herbstman JB;Sjödin A;Kurzon M;Lederman SA;Jones RS;Rauh V;Needham LL;Tang D;Niedzwiecki M;Wang RY;Perera F
通讯作者：
Perera F
影响因子：
11.4
作者：
Johnson, Paula I.;Stapleton, Heather M.;Slodin, Andreas;Meeker, John D.
通讯作者：
Meeker, John D.
影响因子：
10.4
作者：
Athanasiadou M;Cuadra SN;Marsh G;Bergman A;Jakobsson K
通讯作者：
Jakobsson K
影响因子：
3.8
作者：
Dingemans, Milou M. L.;van den Berg, Martin;Westerink, Remco H. S.
通讯作者：
Westerink, Remco H. S.
DOI：
10.1124/jpet.104.068973
发表时间：
2004-10-01
影响因子：
3.5
作者：
Lang, T;Klein, K;Zanger, UM
通讯作者：
Zanger, UM