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*
Center for Nutritional Sciences, Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences and
Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611
2To whom correspondence should be addressed. E-mail: mcmahon{at}ufl.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • biotin • antiepileptic drug • carbamazepine • carboxylase • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–4
).
Although less well appreciated and understood, one of the most prominent nutrient-drug interactions that occur with AED therapy, in terms of both frequency and magnitude, is that with the water-soluble vitamin biotin. In 1982 Krause et al. (5
) recognized that therapy with carbamazepine (CBZ), phenytoin and valproic acid is associated with a reduction in biotin status. Approximately 80% of the epileptics in this study had 50% lower serum biotin than untreated individuals. Epileptics treated with valproate also exhibited a significant, but less severe, reduction in serum biotin. A subsequent study found that urinary excretion of the organic acids 3-hydroxyisovaleric acid (3-HIA) and lactic acid [associated with insufficient 3 methylcrotonyl CoA carboxylase (MCC) and pyruvate carboxylase (PC) activity] was elevated in individuals treated with CBZ and/or phenytoin, but not with valproate, suggesting a loss of biotin-dependent enzyme function (6
). Finally, a third study analyzed an additional 404 AED-treated individuals and found similar reductions in serum biotin (7
). Although lending substantial weight to the evidence of an AED-biotin interaction, these studies were potentially limited by the technique used to measure biotin, which lacks chemical specificity (8
). Additionally, serum biotin may be limited as a useful indicator of biotin status in humans (9
). A later study, however, confirmed these earlier clinical observations by demonstrating an increase in the urinary excretion of 3-HIA, a marker of 3-MCC activity and a validated index of biotin status in AED-treated individuals (10
).
Potential mechanisms to account for the reduction in serum biotin induced by AED therapy have been investigated. CBZ and phenytoin have been shown to accelerate biotin catabolism (10
). One likely explanation of this phenomenon is that the hepatic enzyme systems that are responsible for CBZ catabolism and are autoinduced during anticonvulsant therapy also act on biotin. In addition to accelerated biotin degradation, CBZ competitively inhibits biotin absorption in rat intestinal membrane vesicle preparations, suggesting that dietary absorption of biotin may be reduced during AED therapy (11
). The competitive inhibition of biotin absorption is most likely explained through structural similarities between CBZ and biotin (Fig. 1
) (11
). Together, these studies support the hypothesis that individuals treated with CBZ, phenytoin, primidone and structurally related compounds are biotin deficient.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats were obtained from Harlan (Indianapolis, IN). Purified biotin-free rat diet based on a modified AIN 76a formulation described previously was obtained from Research Diets (New Brunswick, NJ) (12
). 5-Ethyl-5-p-tolybarbituric acid, CBZ, CBZ 10,11-epoxide (CBZ-e), D-biotin, protease inhibitor cocktail and o-phenylenediamine dihydrochloride were purchased from Sigma-Aldrich (St. Louis, MO); avidin-horseradish peroxidase was purchased from Pierce Chemical Company (Birmingham, AL); 96-well microtiter plates (Nunc Maxisorb) and bovine serum albumin were purchased from Fisher Scientific (Pittsburgh, PA). Enhanced chemiluminescence reagent (ECL-Plus) was purchased from Amersham Pharmacia (Piscataway, NJ). Biotinylated bovine serum albumin and avidin-AlexaFluor 430 conjugate were synthesized as previously described (12
).
Animals and dietary treatments.
Male Sprague Dawley rats (n = 20), 50–74 g initial weight, were housed individually in hanging wire-bottom cages in an environmentally controlled room with a constant temperature (22°C) and a 12-h light:dark cycle. The animals were fed a modified AIN 76a diet containing 0.06 mg biotin/kg diet for 5 d before the study to standardize their biotin status as previously described (12
). This diet includes spray-dried egg white as its sole protein source. The protein avidin, contained within the egg white, binds 
1.44 mg biotin/kg purified diet. The amount of dietary biotin reported in these experiments represents that in excess of the biotin binding capacity of avidin as determined by the HPLC-avidin binding assay previously described (12
). On d 5, rats were divided into three dietary treatment groups receiving 0 g CBZ/kg diet (n = 10), 1.5 g CBZ/kg diet (n = 5) or 2.9 g CBZ/kg diet (n = 5) for the next 19 d. On d 12, 19 and 23, rats were placed in metabolic cages for 3 h to allow the discrete collection of urine. On d 24, they were anesthetized under halothane vapor and killed by exsanguination. Brain, liver and serum were collected and prepared as described below. All procedures were approved by the University of Florida Animal Care and Use Committee.
Sample preparation.
After anesthesia, whole blood was withdrawn, allowed to coagulate for 30 min, and centrifuged at 10,000 x g for 5 min to collect serum. Whole brain and liver (500 mg) were removed and homogenized in 10 volumes of ice-cold homogenization buffer [300 mmol/L mannitol, 10 mmol/L HEPES (pH 7.2), 1 mmol/L EDTA and protease inhibitor cocktail]. A portion of the homogenate was set aside for protein biotinylation analysis and the remainder was centrifuged at 200,000 x g for 30 min at 4°C to collect the soluble fraction. All samples were immediately frozen in a mixture of dry ice and isopropanol and stored at -80°C until needed.
Competitive binding assay of biotin.
Biotin and its metabolites in urine, serum, liver and brain were measured with a coupled HPLC/competitive binding assay as previously described, with minor modifications (13
–15
).
Detection and quantification of biotinylated proteins.
The five biotin-dependent carboxylases, acetyl CoA carboxylase (ACC) isoforms 1 and 2, PC, propionyl CoA carboxylase (PCC), and MCC were detected using the avidin blotting technique described previously, with slight modifications (12
). Because of their similar molecular weights, PCC and MCC are not well separated under normal SDS-PAGE conditions (10% separating gel, pH 8.8). Using an 8% separating gel at pH 8.0, superior resolution is achieved so that individual quantification of each carboxylase could be accomplished (data not shown). The specificity and linearity of this detection have been previously demonstrated (12
).
Measurement of CBZ and CBZ-e.
Urine, serum and tissue CBZ and CBZ-e were measured using a method described previously (16
). One gram of diet was mixed with 5 mL of acetone containing 10 mg of 5-ethyl-5-p-tolybarbituric acid/L and vortexed 10–15 min. This mixture was centrifuged at 13,000 x g for 10 min and the soluble fraction was recovered for analysis. Urine and serum were prepared by mixing an equal volume of acetone containing tolylbarbituric acid (10 mg/L) and centrifuging at 13,000 x g for 5 min. Tissues were prepared by homogenizing in 10 volumes ice-cold homogenization buffer (10 mmol/L HEPES, 300 mmol/L mannitol, 1 mmol/L EDTA and protease inhibitor cocktail, pH 7.2) using a Polytron homogenizer and centrifugation at 200,000 x g for 30 min at 4°C. The soluble fraction was recovered and mixed with an equal volume of acetone containing 10 mg tolylbarbituric acid/L, and then the sample was centrifuged at 13,000 x g for 5 min at room temperature. The soluble fractions from these samples were then mixed with two volumes of dichloromethane and vortexed, and the aqueous phase was removed. The organic layer was dried at 65°C and resuspended in methanol. All samples were filtered using a 0.5-µm filter immediately before injection into the HPLC. The reversed phase column used was a Luna 5-µm C18, 250 x 2 mm (Phenomenex, Torrance, CA) with a mobile phase of 17% acetonitrile, 55% methanol and 28% 0.4 mmol/L potassium phosphate (pH 6). Eluted compounds were detected by ultraviolet absorption at 195 nm. Known amounts of CBZ or CBZ-e were separated and a peak area ratio was determined to generate a standard curve.
Measurement of biotin-dependent enzyme activity.
PC activity was measured by a modification of the method described previously (17
). The assay mixture contained in a final volume of 0.1 mL 100 mmol/L Tris HCl (pH 8.0), 3.8 mmol/L MgCl2, 3.14 mmol/L adenosine triphosphate, 0.32 mmol/L acetyl CoA, 0.5% Triton X-100, 7.5 mmol/L freshly prepared pyruvate and 4 mmol/L [14C]NaHCO3 (specific activity, 0.9 mCi/mmol). Blanks were prepared by omitting pyruvate from the reaction mixture. Equal aliquots of the crude homogenate (0.1 mg) were added and allowed to incubate at 37°C for 15 min. PC activity was linear for at least the first 25 min. The reaction was stopped by adding 0.05 mL of 200 g/L trichloroacetic acid and the precipitated protein was centrifuged at 5000 x g for 5 min. The supernatant was transferred to a scintillation vial and 0.1 mL of 100 g/L trichloroacetic acid was added to wash the protein pellet. The pellet was centrifuged at 5000 x g for 5 min and the supernatant was added to the corresponding scintillation vial. The pooled supernatants were dried under a stream of nitrogen at 65°C for 30 min and resuspended in 0.5 mL of distilled water. Five milliliters of scintillation counting cocktail was added to each vial and the samples were counted by liquid scintillation counting. Specific activities were expressed as pmol oxaloacetate formed · mg protein-1 · min-1.
Statistical analysis.
Results are expressed as mean ± SD. The significance of differences (P < 0.05) was tested by one-way ANOVA with Newman-Keuls post test. For some analyses, differences between the two drug levels were assessed by t test at each time point. Homogeneity of variance was routinely verified and no data transformation was necessary for these experiments.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After mixing of crystalline CBZ into the semipurified diet, analysis indicated dosage levels of 1.5 and 2.9 g CBZ/kg diet. Over the 19-d course of treatment, rats consuming the CBZ-containing diets exhibited growth rates and food intakes not significantly different from controls consuming the purified diet alone (Fig. 2
). After 1 wk of consuming the CBZ-containing diets, urinary CBZ excretion in rats fed the 2.9 g/kg diet was significantly higher than in those fed the 1.5 g/kg diet. Urinary CBZ excretion was not different between dietary groups for the remainder of the study (Fig. 3A
). The urinary excretion of CBZ-e was significantly greater for rats fed the 2.9 g/kg diet than for those fed the 1.5 g/kg diet at all time points (Fig. 3
B). At the end of study, serum CBZ concentration was not different between the two drug treatment groups (3.9 ± 0.72 and 4.9 ± 0.16 µmol/L for the 1.5 and 2.9 g CBZ/kg groups, respectively). Brain CBZ concentration was significantly higher in the rats fed 2.9 g/kg than in the 1.5 g/kg group (Fig. 3
C). Hepatic CBZ concentration was similar to that in the brain but was not different between the 1.5 and 2.9 g/kg groups (Fig. 3
D).
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In rats consuming the diet containing 2.9 g CBZ/kg, brain ammonia levels were significantly elevated compared with those consuming either no CBZ or 1.5 g/kg (Fig. 4A
). Brain lactate concentration was likewise elevated in rats consuming diet containing either level of CBZ compared with controls (Fig. 4
B). Consumption of diets containing CBZ did not affect hepatic lactate concentration (Fig. 4
C).
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Urinary biotin excretion was significantly reduced in rats consuming 1.5 g CBZ/kg but was elevated in those fed 2.9 g CBZ/kg (Fig. 5A
). Consumption of CBZ-containing diets had no effect on serum biotin concentration but elevated the concentration of biotin sulfoxides and biocytin (Fig. 5
B). The concentrations of bisnorbiotin and biocytin were significantly reduced in the brains of rats consuming either 1.5 or 2.9 g CBZ/kg diet (Fig. 5
D). There was no effect of dietary CBZ on hepatic biotin, biotin sulfoxides or biocytin at the two levels tested (Fig. 5
C).
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As assessed by avidin blotting, the abundance of biotinylated PC was reduced 25% (P < 0.05) in the brains of rats consuming 1.5 or 2.9 g CBZ/kg, whereas the abundances of biotinylated PCC, MCC or ACC were not affected (Fig. 6
). The relative abundance of hepatic biotinylated PC was significantly reduced by 25 and 39% in rats consuming the 1.5 and 2.9 g/kg diets, respectively. Hepatic ACC1 and ACC2 were reduced in the rats consuming both dietary levels of CBZ compared with controls [41 and 25% for ACC1 and 40 and 38% for ACC2 (P < 0.05) for the 1.5 and 2.9 g/kg diet groups, respectively) (Fig. 7
). Hepatic MCC and PCC abundances were reduced by 17 and 11% (P < 0.05), respectively, in rats consuming the 2.9 g/kg diet compared with controls (Fig. 7)
.
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To determine whether the observed reduction in carboxylase abundance is consistent with a reduction in enzymatic activity, the function of hepatic PC in rats consuming the 0 g CBZ/kg and 2.9 g CBZ/kg diets was measured. The activity of hepatic PC was reduced 32% in rats consuming 2.9 g CBZ/kg diet compared with control rats (3.7 ± 0.23 versus 5.1 ± 0.91 nmol · mg-1 · min-1, P < 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). This was an important consideration in light of the results by Said et al. (11
), who demonstrated that one mechanism by which CBZ might reduce biotin status is competitive inhibition of intestinal biotin absorption. Second, we observed no reductions in food intake or growth rate, demonstrating the tolerability of the drug when mixed with the AIN 76A diet. Furthermore, we observed the well established phenomenon of autoinduction of catabolism, evidenced by the substantial reduction in urine drug concentration after the first week of consumption. One potentially important consideration of these studies is that the dietary level of CBZ used achieved circulating drug concentrations somewhat lower than we designed, resulting in a model that could be considered subclinical. This could partially explain the lack of toxicity that has been observed in other studies using dietary CBZ (19
). This also suggests, however, that the effects of dietary CBZ observed in this study should be viewed as conservative in relation to what could occur at higher dosages.
In agreement with earlier studies, we observed changes in the level of biotin metabolites consistent with altered biotin catabolism. Oral consumption of CBZ elevated both biotin sulfoxides and bisnorbiotin, suggesting that the two major pathways of biotin catabolism (sulfur oxidation and ß-oxidation) were induced, in general agreement with earlier reports (20
).
Elevation of circulating organic acids, such as lactic acid, is a common clinical finding in individuals treated with various AED (6
,21
). Although we observed no such elevation in serum lactate, brain lactate was significantly increased. Independence of these two compartments of the body is in agreement with earlier observations (22
). One likely explanation for the increase in brain lactate is that CBZ reduced the abundance of biotinylated PC, leading to a reduced enzymatic capacity to maintain the citric acid cycle intermediates. This could lead to an increase in pyruvate, which might increase the flux to lactate through lactate dehydrogenase. Loss of PC activity has been previously associated with elevation of lactate (23
,24
). The loss of PC activity can be explained at least in part by a reduction in the abundance of brain biotinylated PC. This provides strong evidence that either the abundance of the PC polypeptide or the biotinylation of the polypeptide is reduced in CBZ-treated rats. A lactic acid buildup in the brain is of particular concern, because lactate exhibits low permeability across the blood-brain barrier and can act as a toxin in other tissues (25
,26
). Additionally, lactic acidemia is associated with impaired neurological function. Elevated lactic acid levels are observed in the brain of piglets with experimentally induced convulsions and in the extracellular fluid of the hippocampus of humans during spontaneous seizures (27
,28
). Lactate levels were also higher in the cerebral spinal fluid of status epileptics than that of control individuals (29
).
Similarly, the elevation in 3-HIA that has been observed in CBZ therapy is explained by the reduction in the abundance of the biotinylated form of MCC, which is responsible for the catabolism of leucine (Fig. 7)
. Reduction in methylcrotonyl CoA activity is associated with accumulation and excretion of the resulting 3-HIA (30
–33
).
The dietary administration of CBZ also elevated brain ammonia, which was unexpected because of the labile nature of this metabolite. Two mechanisms can be proposed to account for this elevation. The first is that biotin deficiency has been shown to reduce the expression and activity of ornithine transcarbamoylase, a critical enzyme in the urea cycle (34
). This inhibition of the urea cycle has been proposed to account for the hyperammonemia observed during biotin deficiency. However, because we observed no marked reduction in biotin status, this may be an unlikely mechanism. A second plausible explanation is the observation that leucine is an allosteric activator of glutamate dehydrogenase, the enzyme that catalyzes production of ammonia (35
). It is reasonable to predict leucine metabolism would be impaired in hepatocytes with decreased abundance of 3-MCC, although this has not been directly determined.
Reductions in the abundance of biotinylated ACC isoforms and PCC have additional ramifications for metabolic alterations during CBZ therapy. Simultaneous reductions in ACC1 and ACC2 would promote a shift in hepatocytes from fatty acid synthesis to fatty acid oxidation. A reduction in the abundance of the cytosolic ACC1 limits the ability to synthesize fatty acids de novo, and is associated with elevations in odd chain fatty acids (36
–40
). A concurrent reduction in the abundance of the outer mitochondrial membrane protein ACC2 would promote fatty acid oxidation by lowering the barrier to entry of fatty acids into the mitochondrial matrix (41
–43
). Although the reduction in enzyme abundance observed in these experiments is consistent with this interpretation, direct functional evidence is needed. Hepatocytes also contained less biotinylated PCC in rats fed CBZ (Fig. 7)
, limiting the enzymatic capacity to catabolize select amino acids, cholesterol and odd chain fatty acids. Again, although these results are strongly suggestive, positive functional data are required to substantiate these findings.
Taken together, these data suggest that oral administration of CBZ reduces the abundance of the biotinylated, and therefore functional, form of biotin-dependent enzymes, even when the CBZ is administered with food. Furthermore, this effect is also evident in the rat brain, where the metabolic derangement results in accumulation of lactate and ammonia, both potentially neurotoxic intermediates. The reduction in abundance of the biotinylated carboxylases could arise from either reduction in the abundance of the polypeptide or reduced biotinylation of each carboxylase, and the mechanisms involved require further investigation.
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FOOTNOTES |
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3 Abbreviations used: 3-HIA, 3-hydroxyisovaleric acid; ACC, acetyl CoA carboxylase; AED, antiepileptic drug; CBZ, carbamazepine; CBZ-e, CBZ 10,11-epoxide; MCC, methylcrotonyl CoA carboxylase; PC, pyruvate carboxylase; PCC, propionyl CoA carboxylase.
Manuscript received 22 May 2002. Initial review completed 7 July 2002. Revision accepted 7 August 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Krause, K. H., Berlit, P., Bonjour, J. P., Schmidt-Gayk, H., Schellenberg, B. & Gillen, J. (1982) Vitamin status in patients on chronic anticonvulsant therapy. Int. J. Vitam. Nutr. Res. 52:375-385.[Medline]
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3. Carl, G. F., Eto, I. & Krumdieck, C. L. (1987) Chronic treatment of rats with primidone causes depletion of pteroylpentaglutamates in liver. J. Nutr. 117:970-975.
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43. Abu-Elheiga, L., Jayakumar, A., Baldini, A., Chirala, S. S. & Wakil, S. J. (1995) Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms. Proc. Natl. Acad. Sci. USA 92:4011-4015.
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