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Nutrient-Gene Interactions

Dietary Carbamazepine Administration Decreases Liver Pyruvate Carboxylase Activity and Biotinylation by Decreasing Protein and mRNA Expression in Rats

Sara C. Rathman^*,, Raymond K. Blanchard^*,, Lokenga Badinga^**, Jesse F. Gregory, III^*,, Stephan Eisenschenk and Robert J. McMahon^*,,2

^* Center for Nutritional Sciences, Food Science and Human Nutrition Department, ^** Department of Animal Sciences and Department of Neurology, University of Florida, Gainesville, FL 32611

²To whom correspondence should be addressed at 2400 West Lloyd Expressway, Mail Stop R10, Mead Johnson Nutritionals, Evansville, IN 47221-0001. E-mail: robert.j.mcmahon{at}bms.com.

Clinical data demonstrate that certain antiepileptic drugs including carbamazepine (CBZ) decrease serum biotin concentration 45–50% and increase urine and serum organic acids, which is suggestive of reduced function of biotin-dependent enzymes. However, little is known about biotin-dependent enzyme function at the tissue level in patients undergoing long-term CBZ treatment. We recently established that dietary CBZ administration to rats increases brain lactate and also decreases specific enzymatic activity and the relative abundance of hepatic biotinylated pyruvate carboxylase (PC). To examine the mechanism of altered activity and abundance of biotinylated PC, the effect of orally administered CBZ on hepatic PC protein and mRNA expression was examined in rats consuming a physiologically relevant level of dietary biotin (0.06 mg/kg). Rats were fed 0 or 3.4 g CBZ/kg diet for 28 d, a dose designed to achieve clinically relevant serum CBZ concentrations. Hepatic biotinylated PC and PC activity were significantly reduced by 43 and 30%, respectively, in the drug-treated group. Liver PC protein expression and mRNA were 43 and 35% lower, respectively, in the drug-treated group than in controls. Brain biotinylated PC was significantly lower (29%), whereas specific enzymatic activity was 175% higher in rats consuming the 3.4 g CBZ/kg diet. Brain, but not serum, lactate was significantly higher in rats consuming CBZ. Taken together, the lower PC protein and mRNA expression provide a plausible biochemical mechanism to explain the decreased abundance of biotinylated hepatic PC observed in previous studies.

KEY WORDS: • carbamazepine • biotin • rats • antiepileptic drug • pyruvate carboxylase

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