Metabolism of Polybrominated Diphenyl Ethers (PBDEs) by Human Hepatocytes in Vitro

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that accumulate in human tissues and are potential toxicants. Concentrations of PBDEs in human tissues have increased recently, and body burdens in the U.S. and Canadian populations are higher than in any other region. OBJECTIVES: Although metabolism in animal laboratory studies has been examined, no studies have explored the metabolism of these contaminants in human tissues. We undertook this study to determine whether PBDEs could be metabolized by human liver cells in vitro and to identify what types of metabolites are formed. METHODS: We exposed hepatocytes from three different donors (two cryopreserved batches and one fresh batch) to solutions containing 10 mu M of either of two environmentally relevant and prominent PBDE congeners-BDE-99 or BDE-209-for periods of 24-72 hr. We also conducted gene expression analysis to provide information on potential induction of xenobiotic metabolizing enzymes. RESULTS: Exposing hepatocytes to BDE-99 resulted in the formation of 2,4,5-tribromophenol, two morohydroxylated pentabrominated diphenyl ether metabolites, and a yet unidentified tetrabrominated metabolite. No hydroxylated or debrominated metabolites were observed in the cells exposed to BDE-209. This suggests that BDE-209 was not metabolized, that nonextractable, covalently protein-bound metabolites were formed, or that the exposure time was not long enough for BDE-209 to diffuse into the cell to be metabolized. However, we observed up-regulation of genes encoding for cytochrome P450 monooxygenase (CYP) 1A2, CYP3A4, deiodinase type 1, and glutathione S-transferase M1 in hepatocyes exposed to both BDE-99 and BDE-209. CONCLUSIONS: Our in vitro results suggest that the human liver will likely metabolize some BDE congeners (e.g., BDE-99) in vivo. These metabolites have been shown to elicit greater toxicity than the parent BDE congeners in laboratory bioassays; thus, more research on body burdens and human health effects from these metabolites are warranted.