Unknown

Dataset Information

0

Biotransformation of BDE-47 to potentially toxic metabolites is predominantly mediated by human CYP2B6.


ABSTRACT:

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.

SUBMITTER: Feo ML 

PROVIDER: S-EPMC3620761 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Biotransformation of BDE-47 to potentially toxic metabolites is predominantly mediated by human CYP2B6.

Feo Maria Luisa ML   Gross Michael S MS   McGarrigle Barbara P BP   Eljarrat Ethel E   Barceló Damià D   Aga Diana S DS   Olson James R JR  

Environmental health perspectives 20121218 4


<h4>Background</h4>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.<h4>Objectives</h4>The purposes of this study were to characterize the in vitro metabolism of 2,2´,4,4´-tetrabromodiphenyl  ...[more]

Similar Datasets

| S-EPMC6317432 | biostudies-literature
| S-EPMC5897322 | biostudies-literature
| S-EPMC6542340 | biostudies-literature
| S-EPMC4024654 | biostudies-literature
| S-EPMC3908718 | biostudies-literature
| S-EPMC3528349 | biostudies-literature
2018-09-01 | GSE104896 | GEO
| S-EPMC4018524 | biostudies-literature
2018-09-01 | GSE115399 | GEO
| S-EPMC8402933 | biostudies-literature