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Xenobiotics such as phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and Aroclor 1254 significantly suppress the activity of a key gluconeogenic and glyceroneogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), suggesting that xenobiotics disrupt hepatic glucose and fat metabolism. The effects of polybrominated diphenyl ethers (PBDE), a family of synthetic flame-retardant chemicals, on PEPCK activity is unknown. This study investigated the effect of DE-71, a commercial PBDE mixture, on PEPCK enzyme kinetics. Forty-eight 1-mo-old male Wistar rats were gavaged daily with either corn oil or corn oil containing 14 mg/kg DE-71 for 3, 14, or 28 d (n?=?8/group). At each time point, fasting plasma glucose, insulin, and C-peptide were measured and hepatic PEPCK activity, lipid content, and three cytochrome P-450 enzymes (CYP1A, -2B, and -3A) were assayed. PBDE treatment for 28 d significantly decreased PEPCK Vmax (mu mol/min/g liver weight) by 43% and increased liver lipid by 20%, compared to control. CYP1A, -2B, and -3A Vmax values were enhanced by 5-, 6-, and 39-fold, respectively, at both 14 and 28 d in treated rats compared to control. There was a significant inverse and temporal correlation between CYP3A and PEPCK Vmax for the treatment group. Fasting plasma glucose, insulin, and C-peptide levels were not markedly affected by treatment, but the glucose:insulin ratio was significantly higher in treated compared to control rats. Data suggest that in vivo PBDE treatment compromises liver glucose and lipid metabolism, and may influence whole-body insulin sensitivity.