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,**,2
* Center for Nutritional Sciences,
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611 and
** Mead Johnson Nutritionals, Evansville, IN 47721
2To whom correspondence should be addressed. E-mail: bob.mcmahon{at}bms.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • carbamazepine • biotin • rats • lactate • pyruvate carboxylase
Carbamazepine (CBZ)2 is most widely used as an antiepileptic drug (AED) to treat partial and secondarily generalized seizures (1). Over 80% of epileptics taking AED such as CBZ exhibit some degree of biotin deficiency (2). Several studies indicate that plasma biotin is reduced 45–50% in patients taking AED compared with untreated individuals (3,4). Adults and children undergoing long-term AED therapy experience elevated organic acids in their urine including lactic acid and 3-hydroxyisovaleric acid, which are also indicative of decreased function of biotin-dependent enzymes (3,5,6). Biotin deficiency induced by CBZ and other AED is likely due to the drug and not the disease itself because biotin depletion occurs only after initiation of AED treatment (3,4). CBZ and other AED, including primidone with a common ureido group structurally similar to biotin, competitively inhibit biotin uptake across the intestinal brush border in vitro (7). AED with ureido groups also accelerate catabolism of biotin to its inactive catabolites, bisnorbiotin (BNB) and biotin sulfoxide (BSO), in both adults and children undergoing long-term AED therapy (5,6). Along with decreased uptake of biotin, accelerated catabolism likely contributes to the mechanism of decreased biotin status during AED therapy.
A previous animal study from our laboratory indicated that 2.9 g CBZ/kg diet fed to rats for 21 d decreased specific enzymatic activity and abundance of hepatic biotinylated pyruvate carboxylase (PC) (8). These changes were accompanied by an elevation of brain lactate (8), a product that has been shown to accumulate when PC activity is decreased (9–12). Decreased PC activity can lead to an accumulation of pyruvate, which might increase the flux to lactate through lactate dehydrogenase. If the elevated serum and urine lactate observed in epileptic patients treated with AED (3) and in the brain of rats treated with CBZ (8) is due to decreased PC activity, then increasing PC activity should decrease lactate concentration. In previous studies, biotin supplementation to biotin-deficient primary culture hepatocytes or biotin-deficient chicks increased PC activity (13,14). This suggests that biotin supplementation could increase flux to pyruvate by increasing PC activity, thereby decreasing brain lactate in CBZ-treated rats. In this investigation, we supplemented CBZ-treated rats with a pharmacologic dose of biotin to determine whether biotin supplementation could reduce brain lactate by maintaining biotin status and activity of biotin-dependent enzymes.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats were obtained from Harlan (Indianapolis, IN). Purified biotin-free rodent diet based on a modified AIN76A formulation described previously was obtained from Research Diets (New Brunswick, NJ) (15). CBZ, 5-ethyl-5-p-tolylbarbituric acid, carbamazepine 10,11-epoxide (CBZ-e), D-biotin, protease inhibitor cocktail, [14C]NaHCO3, NADH and o-phenylenediamine dihydrochloride were purchased from Sigma (St. Louis, MO); avidin-horseradish peroxidase (Avidin-HRP) and avidin-alkaline phosphatase (Avidin-AP) were purchased from Pierce Chemical Company (Birmingham, AL); 96-well microtiter plates (Nunc Maxisorb) and bovine serum albumin (BSA) were purchased from Fisher Scientific (Pittsburgh, PA). Enhanced chemifluorescence (ECF) reagent was purchased from Amersham-Pharmacia (Picastaway, NJ). Biotinylated BSA and avidin-AlexaFluor 430 conjugate were synthesized as previously described (16).
Animals and dietary treatments.
Male Sprague-Dawley rats (n = 55), 50–75 g initial weight, were housed individually in hanging wire-bottomed cages in an environmentally controlled room with constant temperature (22°C) and a 12-h light:dark cycle. The rats were acclimated by feeding a powdered, egg-white based modification of the AIN76A diet containing 0.06 mg free biotin/kg diet (16) for 5 d to standardize their biotin status. This modified AIN76A diet contained avidin, a component of egg-white protein, at a concentration sufficient to bind 1.44 mg biotin/kg diet and to render it unavailable for absorption. Thus, to make a diet that contained 0.06 mg of free biotin/kg diet, 1.50 mg biotin/kg diet was added to the diet. The concentration of free biotin was measured using a combined HPLC/competitive assay (16) and was confirmed to be 0.06 mg biotin/kg diet. Part of this diet was prepared with 3.75 g CBZ/kg diet, and HPLC analysis (8) revealed 3.75 g CBZ/kg diet, which confirmed the accuracy of diet formulation. After 5 d of acclimation, 5 rats were killed and serum, liver and brain were collected as described below. The remaining 50 rats were randomly assigned to 2 groups administered either 0 g CBZ/kg diet (n = 25) or 3.75 g CBZ/kg diet (n = 25) for 21 d. Rats (n = 5) from each treatment group were killed on d 26 of the study, and serum, liver and brain were collected. Those from the remaining groups were then divided into two further treatment groups (n = 10) administered either 0.06 mg biotin/kg diet to represent a physiologic dose of biotin or a pharmacologic dose of 6.0 mg biotin/kg diet. This pharmacologic dose of biotin was chosen so that rats would consume a dose of biotin per kilogram body weight similar to that typically administered to patients with biotinidase deficiencies to effectively prevent seizures (17). After 21 d (d 47 of the study) of biotin supplementation, 5 rats from each of the 4 groups were killed and serum, liver and brain were collected. The remaining 5 rats from each group were killed 21 d later and serum, liver and brain were also collected. The entire study was 68 d. Food intake and body weights were recorded every other day. All procedures were approved by the University of Florida Animal Care and Use Committee.
Sample preparation.
On d 5, 26, 47 and 68, rats were anesthetized with halothane and killed by cardiac puncture and exsanguination. Whole blood was allowed to coagulate for 30 min and then centrifuged at 10,000 x g for 5 min to separate serum. Whole brain was removed and homogenized in 10 volumes of ice-cold HEM homogenization buffer (30 mmol/L HEPES, pH 7.2, 1 mmol/L EDTA, 300 mmol/L mannitol and protease inhibitor cocktail). The left lobe of the liver was divided into 5 sections and all samples were immediately frozen in liquid nitrogen and stored at -80°C until analyzed. For protein assays and metabolite analysis, a frozen liver portion was thawed and homogenized in 10 volumes of ice-cold HEM. A portion of each homogenate was saved for protein analysis and the remainder was centrifuged at 200,000 x g for 30 min at 4°C to collect the soluble fraction for measurement of biotin, biotin metabolites and CBZ. All samples were immediately frozen in liquid nitrogen and stored at -80°C until assayed.
Pyruvate carboxylase and acetyl CoA carboxylase (ACC) activity assays.
PC activity in brain and liver was determined using a method previously described (18) with slight modifications (8). For the experiment to determine whether NADH is an activator of PC activity, the reaction mixture was similar to the modified method (8), except 0–2.5 mmol/L NADH was added. Background activity was determined by omitting pyruvate from the reaction mixture. Specific enzymatic activity for PC was expressed as nmol oxaloacetate (OAA) formed/(mg protein · min).
ACC activity was determined using a method described by Thampy et al. (19) with minor modifications. Briefly, frozen liver was homogenized in 10 volumes of homogenization buffer (50 mmol/L potassium phosphate, pH 7.4, 10 mmol/L EDTA, 2 mmol/L dithiothreitol, protease inhibitors) using a Polytron homogenizer. To measure activity, each tube contained 0.1 mg of either liver or brain homogenate, along with a mixture consisting of 50 mmol/L potassium phosphate, pH 7.4, 2.5 mmol/L MgCl2, 2 mmol/L dithiothreitol, 1.17 mmol/L acetyl CoA, 4 mmol/L ATP, 12.5 mmol/L [14C] NaHCO3 (specific activity 40.7 MBq/mmol), 0.75 g/L BSA and 10 mmol/L citrate in a final volume of 0.15 mL. After 15 min at 37°C, the reaction was terminated by adding 0.05 mL 200 g/L trichloroacetic acid (TCA), and the precipitated protein was sedimented by centrifugation at 13,000 x g for 5 min. The supernatant was transferred to a scintillation vial and 0.1 mL of 100 g/L TCA was added to wash the protein pellet. After centrifugation (13,000 x g, 5 min), the supernatant was combined with the initial extract. Pooled supernatants were dried under a stream of nitrogen at 65°C for 30 min and dissolved in 0.5 mL distilled water. Scintillation cocktail (5 mL) was added to each vial and the samples were counted by liquid scintillation counting. Specific enzymatic activity for ACC was expressed as pmol malonyl CoA formed/(mg protein · min).
Detection of biotinylated biotin-dependent carboxylases.
The five biotin-dependent carboxylases, ACC isoforms 1 and 2 (ACC1, ACC2), PC, propionyl CoA carboxylase (PCC) and methylcrotonyl CoA carboxylase (MCC) were detected using the avidin blotting technique described previously with slight modifications (16). Because of their similar molecular weights, PCC and MCC are not separated under SDS-PAGE conditions used for the other carboxylases (10% total acrylamide, pH 8.8, separating gel). Using an 8% separating gel (total acrylamide) at pH 8.0, superior resolution is achieved so that individual quantification of both MCC and PCC can be accomplished (Fig. 1).
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The measurement of biotin and its metabolites in serum, liver and brain was performed using a coupled HPLC/competitive binding assay (16,20). Serum, liver, brain and dietary CBZ were measured using a method previously described (21) with slight modifications (8).
NADH was measured using a method described by Uppal and Gupta (22). NADH concentration from brain samples was determined by extrapolation from a standard curve with known NADH concentrations. Serum and tissue lactate concentrations were measured using a kit based on the spectrophotometric endpoint method of measuring NADH (Sigma Diagnostics, St. Louis, MO).
Statistical analysis.
Results are expressed as means ± SD. Differences in concentrations of biotin and biotin metabolites among treatments were tested using a Student’s t test on d 26 (2 treatment groups) and a two-way ANOVA for data from d 47 and 68 (with biotin intake and CBZ exposure as main factors). Data for biotinylated carboxylases and lactate from d 68 of the study were tested using a two-way ANOVA (with biotin intake and CBZ exposure as the main factors). Comparisons of CBZ concentrations between control and biotin-supplemented groups were conducted using a Student’s t test. In all statistical procedures, a differences were considered significant at P < 0.05. Homogeneity of variance was routinely verified and no data transformation was necessary for these experiments.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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CBZ reduced serum biotin by 60% after d 47 (P < 0.05), and biotin supplementation (6 mg/kg diet) prevented this decrease (Table 1). Although biotin supplementation increased serum biotin in both control and CBZ-treated groups, serum biotin in the controls was 83% higher than in the CBZ-treated group. Like the response for serum, hepatic biotin was reduced in CBZ-treated rats by 
50% compared with controls (P < 0.05) (Table 1), whereas biotin supplementation prevented the decrease of free hepatic biotin concentration in these rats. In contrast, CBZ treatment did not alter brain biotin concentration. Biotin supplementation increased brain biotin concentration in both groups; however, the elevation was 12% less in the CBZ-treated group than in the controls on d 68 (Table 1).
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123% compared with controls on d 47 but there was no difference on d 68. Biotin supplementation also increased hepatic BSO in both groups. In contrast, CBZ decreased brain BSO by 40% on d 26 (P < 0.05) but did not have an effect on d 47 and 68 (Table 1). CBZ also increased biotin catabolism to the inactive catabolite, BNB. CBZ administration increased serum BNB concentration consistently over time (Table 1). Serum BNB was elevated 27, 163 and 410% on d 26, 47 and 68, respectively, in the drug-treated group compared with controls. CBZ also increased both hepatic and brain BNB by the end of the study (68 d). Biotin supplementation elevated serum BNB in both groups and by d 68, CBZ-treated rats had serum BNB concentration equal to biotin-supplemented controls and CBZ-treated rats. Biotin supplementation similarly elevated brain and hepatic BNB in control and CBZ-treated rats (Table 1). CBZ had no effect on hepatic or brain biocytin, and biotin supplementation similarly had no effect in these tissues; however, biotin supplementation increased serum biocytin 146% in control rats but only 116% in CBZ-treated rats on d 47 (Table 1).
Consistent with the biotin depletion observed in the liver and serum associated with CBZ treatment, we observed significantly decreased biotinylated ACC1, ACC2 and PC. However, CBZ had no effect on the abundance of hepatic biotinylated MCC or PCC. Biotinylated ACC1, ACC2, and PC were decreased by 33, 60 and 43%, respectively, in the drug-treated group (Fig. 2). Biotin supplementation prevented the decrease of hepatic biotinylated ACC1 and ACC2 but not PC. All biotin-dependent carboxylases in brain were decreased by CBZ (31, 42, 43 and 43% for PC, MCC, PCC and ACC1, respectively, P < 0.05) but only decreases of biotinylated ACC1 were prevented during biotin supplementation (Fig. 2).
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By d 68 of the study, CBZ increased lactate concentrations in serum (Fig. 5A) and brain (Fig. 5B) but not in liver (Fig. 5C) of rats consuming 0.06 mg biotin/kg diet (P < 0.05). Biotin supplementation (6.0 mg biotin/kg diet) in CBZ-treated rats effectively prevented the increase of lactate in serum and brain (P < 0.05).
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To determine the mechanism by which PC activity increased in brain and liver after biotin supplementation in the CBZ-treated rats, we hypothesized that there were activators of PC in addition to the Mg2+ and acetyl CoA already accounted for in the activity assay. Elevated brain NADH would likely accompany decreased lactate. Because biotin supplementation prevents the increase in brain lactate and therefore maintains NADH concentration, the possibility of NADH being an activator of PC was studied. NADH activated hepatic PC in crude liver homogenates of both control and CBZ-treated rats. The addition of 0.625–1.25 mmol/L NADH to the reaction mixture raised hepatic PC activity of CBZ-treated rats to the level of control rats having no added NADH (Fig. 6).
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On d 68 of the experiment, 42 d of biotin supplementation had not altered brain CBZ (46 ± 2.4 and 44 ± 5.3 nmol/g for rats consuming 0.06 or 6.0 mg biotin/kg diet, respectively), liver CBZ (53 ± 0.7 and 54 ± 0.7 nmol/g for rats consuming 0.06 or 6.0 mg biotin/kg diet, respectively) or serum CBZ (1.5 ± 0.4 and 1.2 ± 0.3 µmol/L for rats consuming 0.06 or 6.0 mg biotin/kg diet, respectively). Alterations in NADH and biotin with biotin supplementation, therefore, are not likely due to altered CBZ concentrations in the body.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In the present study, both biotin and CBZ were incorporated into the diet; therefore, they were consumed simultaneously. This is a clinically relevant design because taking CBZ with meals is recommended to patients. Because biotin and CBZ were consumed together, this provided the greatest chance for the pharmacologic dose of biotin to affect CBZ uptake in the intestine. In view of other studies finding that CBZ competitively inhibits biotin uptake in the intestine (7), there was a possibility that excess biotin may similarly inhibit CBZ uptake. Our results do not support this possibility because CBZ concentrations in serum, brain and liver were unaltered by biotin supplementation.
In CBZ-treated rats, the abundance of biotinylated ACC and PC was decreased in brain and liver. As expected, specific enzymatic activities of these carboxylases also were decreased in CBZ-treated rats because the biotinylated form is the active form of the enzyme. Biotin supplementation maintained the abundance of biotinylated ACC in these tissues; however, the abundance of biotinylated PC in brain and liver remained decreased. Biotin supplementation prevented the CBZ-induced decrease of both ACC- and PC-specific enzymatic activity. The likely mechanism for decreased ACC-specific activity involves decreased biotin nutritional status, leading to underbiotinylation of all apocarboxylase. Biotin supplementation increased the pool of free biotin available to biotinylate any remaining apolipoprotein-ACC and, therefore, increased the amount of the active form of the enzyme. The mechanism is not as easily explained for the elevated brain and hepatic PC-specific enzymatic activity after biotin supplementation because the decrease in abundance of biotinylated PC remained. Although the precise mechanism of increased PC activity without changes in biotinylated PC is not known, changes in the concentration of an activator of PC could explain this phenomenon.
To determine whether elevated brain lactate during CBZ administration in rats (8) was due to decreased biotin status and PC activity, lactate was measured after biotin supplementation in rats administered 3.75 g CBZ/kg diet for 68 d. Serum and brain lactate were elevated 15 and 100%, respectively, in rats consuming CBZ compared with controls, and supplementation with a pharmacologic dose of biotin (6 mg/kg diet) prevented this elevation. The elevation of brain lactate was 10 fold higher than the increase found in our previous study when rats consumed 2.9 g CBZ/kg diet for 21 d. Also noteworthy, biotin supplementation prevented elevated brain and serum lactate in the drug-treated group without altering CBZ concentrations. This is striking evidence that decreased biotin status may in fact be related to elevated lactate in clinical (3) and animal studies (8) and that biotin supplementation can reduce lactate concentration.
Because biotin supplementation decreased lactate concentration in CBZ-treated rats to concentrations similar to control rats, it is plausible that flux to pyruvate was increased or lactate was excreted from the body. Because lactate does not easily cross the blood brain barrier, lactate in the brain was likely to be shunted back at least partially to form pyruvate, a pathway that also involves the formation of NADH. In in vitro analysis, NADH maximally increased PC specific activities 350 and 170% in drug-treated and control groups, respectively, compared with PC activity when measured with no NADH in the reaction mixture (Fig. 6). A limitation of the study concerning the effect of NADH on PC activity is that this study used whole-liver homogenates. Greater specificity concerning such effects and specific kinetic information could be obtained by performing studies using purified rat liver PC. Such studies are currently underway in our laboratory. Along with these preliminary in vitro data showing that NADH activates PC, the observation that biotin supplementation prevented the decrease of brain NADH supports our hypothesis that NADH has a regulatory effect on PC.
The precise mechanism of action of anticonvulsant properties of CBZ is not completely known, but there is evidence showing that CBZ may enhance sodium channel inactivation (25). This stabilizes neuronal membranes pre- and postsynaptically by reducing high frequency repetitive firing of action potentials or by slowing synaptic transmission (25). Another proposed mechanism is the blocking of N-methyl-D-aspartate (NMDA) receptor-mediated events (1). NMDA is a glutamate receptor with involvement in seizure generation. The possibility must be considered whether decreased biotin status contributes to the mechanism of action of the drug. Decreased function of biotin-dependent carboxylases, particularly PC, could result in higher cerebral concentrations of carbon dioxide, which has been shown to raise seizure threshold (26,27). Similarly, excessive carbon dioxide concentrations can induce seizures (28) and, therefore, could account for seizures unresponsive to CBZ. Decreased biotin status and PC activity in the brain could also lead to decreased concentration of OAA, which is an essential precursor for de novo synthesis of aspartate, an excitatory neurotransmitter. One study found a modest decrease in brain aspartate concentration following phenytoin treatment in rats (29). If decreased biotin status is not involved in the mechanism of action, then maintaining biotin status during CBZ therapy could possibly prevent some of the side effects that >50% of patients experience while undergoing CBZ therapy (25).
The protective role of biotin supplementation during CBZ administration on biotin status and biotin-dependent enzyme function was demonstrated in this investigation. These results support the use of biotin supplementation during CBZ administration to help maintain biotin status, function of biotin-dependent enzymes and decrease CBZ-induced lactate accumulation.
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FOOTNOTES |
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3 Abbreviations used: ACC, acetyl CoA carboxylase; AED, antiepileptic drug; BNB, bisnorbiotin; BSA, bovine serum albumin; BSO, biotin sulfoxide; CBZ, carbamazepine; MCC, methylcrotonyl CoA carboxylase; NMDA, N-methyl-D-aspartate; OAA, oxaloacetate; PC, pyruvate carboxylase; PCC, propionyl CoA carboxylase; TCA, trichloroacetic acid.
Manuscript received 8 May 2003. Initial review completed 18 June 2003. Revision accepted 23 June 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Lancaster, J. M. & Davies, J. A. (1992) Carbamazepine inhibits NMDA-induced depolarizations in cortical wedges prepared from DBA/2 mice. Experientia 48:751-753.[Medline]
2. Krause, K. H., Bonjour, J. P., Berlit, P., Kynast, G., Schmidt-Gayk, H. & Schellenberg, B. (1988) Effect of long-term treatment with antiepileptic drugs on the vitamin status. Drug-Nutr. Interact. 5:317-343.
3. Krause, K. H., Bonjour, J. P., Berlit, P. & Kochen, W. (1985) Biotin status of epileptics. Ann. N.Y. Acad. Sci. 447:297-313.[Medline]
4. Krause, K. H., Berlit, P. & Bonjour, J. P. (1982) Impaired biotin status in anticonvulsant therapy. Ann. Neurol. 12:485-486.[Medline]
5. Mock, D. M. & Dyken, M. E. (1997) Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants. Neurology 49:1444-1447.
6. Mock, D. M., Mock, N. I., Nelson, R. P. & Lombard, K. A. (1998) Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J. Pediatr. Gastroenterol. Nutr. 26:245-250.[Medline]
7. Said, H. M., Redha, R. & Nylander, W. (1989) Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am. J. Clin. Nutr. 49:127-131.
8. Rathman, S. C., Eisenschenk, S. & McMahon, R. J. (2002) The abundance and function of biotin-dependent enzymes are reduced in rats chronically administered carbamazepine. J. Nutr. 132:3405-3410.
9. Ahmad, A., Kahler, S. G., Kishnani, P. S., Artigas-Lopez, M., Pappu, A. S., Steiner, R., Millington, D. S. & Van Hove, J. L. (1999) Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am. J. Med. Genet. 87:331-338.[Medline]
10. Merinero, B., Perez-Cerda, C. & Ugarte, M. (1992) Investigation of enzyme defects in children with lactic acidosis. J. Inherit. Metab. Dis. 15:696-706.[Medline]
11. Brun, N., Robitaille, Y., Grignon, A., Robinson, B. H., Mitchell, G. A. & Lambert, M. (1999) Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am. J. Med. Genet. 84:94-101.[Medline]
12. Israels, S., Haworth, J. C., Dunn, H. G. & Applegarth, D. A. (1976) Lactic acidosis in childhood. Adv. Pediatr. 22:267-303.[Medline]
13. Rodriguez-Melendez, R., Perez-Andrade, M. E., Diaz, A., Deolarte, A., Camacho-Arroyo, I., Ciceron, I., Ibarra, I. & Velazquez, A. (1999) Differential effects of biotin deficiency and replenishment on rat liver pyruvate and propionyl-CoA carboxylases and on their mRNAs. Mol. Genet. Metab. 66:16-23.[Medline]
14. Frigg, M. & Wick, H. (1977) Effect of graded biotin levels in the diet on liver pyruvate carboxylase of chicks fed ad libitum and after starvation. Int. J. Vitam. Nutr. Res. 47:57-61.[Medline]
15. Rathman, S. C., Lewis, B. & McMahon, R. J. (2002) Acute glucocorticoid treatment increases urinary biotin excretion and serum biotin. Am. J. Physiol. 282:E643-E649.
16. Lewis, B., Rathman, S. & McMahon, R. (2001) Dietary biotin intake modulates the pool of free and protein-bound biotin in rat liver. J. Nutr. 131:2310-2315.
17. Salbert, B. A., Pellock, J. M. & Wolf, B. (1993) Characterization of seizures associated with biotinidase deficiency. Neurology 43:1351-1355.
18. Suormala, T., Wick, H., Bonjour, J. P. & Baumgartner, E. R. (1985) Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample. Clin. Chim. Acta 145:151-162.[Medline]
19. Thampy, G. K., Haas, M. J. & Mooradian, A. D. (2000) Troglitazone stimulates acetyl-CoA carboxylase activity through a post-translational mechanism. Life Sci 68:699-708.[Medline]
20. Mock, D. M. (1997) Determinations of biotin in biological fluids. Methods Enzymol 279:265-275.[Medline]
21. Szabo, G. K. & Browne, T. R. (1982) Improved isocratic liquid-chromatographic simultaneous measurement of phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and N-desmethylmethsuximide in serum. Clin. Chem. 28:100-104.
22. Uppal, A. & Gupta, P. K. (2003) Measurement of NADH concentration in normal and malignant human tissues from breast and oral cavity. Biotechnol. Appl. Biochem. 37:45-50.[Medline]
23. Krause, K. H., Bonjour, J. P., Berlit, P., Kynast, G., Schmidt-Gayk, H. & Arab, L. (1986) B vitamins in epileptics. Bibl. Nutr. Dieta 38:154-167.
24. Wang, K. S., Mock, N. I. & Mock, D. M. (1997) Biotin biotransformation to bisnorbiotin is accelerated by several peroxisome proliferators and steroid hormones in rats. J. Nutr. 127:2212-2216.
25. Sillanpaa, M. (1996) Carbamazepine. Wyllie, E. eds. The Treatment of Epilepsy. Principles and Practice 2nd ed. 1996:808-823 Williams & Wilkins Baltimore, MD .
26. Morimoto, T., Fukuda, M., Aibara, Y., Nagao, H. & Kida, K. (1996) The influence of blood gas changes on hyperthermia-induced seizures in developing rats. Brain Res. Dev. Brain Res. 92:77-80.[Medline]
27. De Jong, R. H., Wagman, I. H. & Prince, D. A. (1967) Effect of carbon dioxide on the cortical seizure threshold to lidocaine. Exp. Neurol. 17:221-232.[Medline]
28. Williams, K. P. & Singh, A. (2002) The correlation of seizures in newborn infants with significant acidosis at birth with umbilical artery cord gas values. Obstet. Gynecol. 100:557-560.[Medline]
29. Patsalos, P. N. & Lascelles, P. T. (1981) Changes in regional brain levels of amino acid putative neurotransmitters after prolonged treatment with the anticonvulsant drugs diphenylhydantoin, phenobarbitone, sodium valproate, ethosuximide, and sulthiame in the rat. J. Neurochem. 36:688-695.[Medline]
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