Polybrominated diphenyl ethers (PBDEs) are additive flame-retardants used in numerous consumer products, resulting in their presence as widespread environmental contaminants. Although three PBDE mixtures were commercially produced (penta-BDE, octa-BDE, and deca-BDE), the lower brominated mixture, penta-BDE, contains the more persistent, bioaccumulative, and toxic congeners. Recent studies have suggested that hydroxylated metabolites of PBDEs accumulate in human serum at levels similar to or greater than their parent PBDEs. Furthermore, bioactivation through oxidative metabolism may increase the neurotoxic potential of PBDEs, however, insufficient data exists on the metabolism of PBDEs in humans. The objectives of this study were to qualitatively and quantitatively characterize the in vitro metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',6-pentabromodiphenyl ether (BDE-100), two of the most abundant PBDEs found in humans, by recombinant human cytochrome P450s (CYPs) and pooled human liver microsomes (HLMs). Recombinant human CYPs (1A1, 1A2, 2A6, 3A4, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1) were individually incubated with 20 �M BDE-47 or BDE-100 to monitor CYP-specific metabolism. CYP2B6 was found to be the predominant CYP responsible for nearly all formation of monohydroxylated-BDE and dihydroxylated-BDE metabolites identified for BDE-47 and BDE-100. CYP2B6 is expressed in the liver and brain and is highly polymorphic among humans. Therefore, interindividual variability of the in vitro metabolism of BDE-47 and BDE-100 was assessed using CYP2B6 genotyped HLMs and recombinant polymorphic variants of CYP2B6 (*4, *5, *6, *7, and *18). Preliminary results indicate that CYP2B6 variants express different catalytic activity towards BDE-47 and BDE-100. Kinetic studies of BDE-47 and BDE-100 metabolism (0-60 �M) suggest that CYP2B6 has a high affinity for the formation of monohydroxylated-BDEs. Our results will ultimately better inform future mechanistic and epidemiological studies investigating the potential of PBDEs and their metabolites to produce neurobehavioral/neurodevelopmental disorders. (Supported in part by NIEHS, grant #ES021554)

Predominant role of human CYP2B6 in the oxidative metabolism of BDE-47 and BDE-100 to potentially toxic metabolites

246th National Meeting (2013)

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