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,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.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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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
Carbamazepine (CBZ) was originally developed for the treatment of trigeminal neuralgia, but it is also currently used to treat epilepsy, bipolar disorders and various pain syndromes. It is presently one of the most widely prescribed antiepileptic drugs (AED) to treat partial and secondarily generalized seizures (1). More than half of the patients taking CBZ experience negative side effects that diminish the quality of life, including allergic dermatological reactions, neurological symptoms and altered nutrient status (2). Although the causes of these side effects are poorly understood, altered nutrient status during AED therapy may be a contributing factor. Although decreased folate, vitamin D and vitamin B-12 status have been observed during AED therapy, biotin deficiency is the most profound vitamin deficiency observed in epileptics (3). According to Krause et al. (3), >80% of epileptics undergoing long-term AED therapy examined exhibit some degree of biotin deficiency. Several studies indicate that plasma biotin is 45–50% lower in patients taking AED than in untreated individuals (4,5). Additional supporting evidence of biotin deficiency during AED therapy includes increased organic acids such as lactic acid and 3-hydroxyisovaleric acid in the urine of both adults and children undergoing long-term AED therapy (4,6,7).
Even a marginal biotin deficiency may have profound effects on epileptics because of the importance of biotin for normal brain structure and function. Biotin is an essential cofactor for pyruvate carboxylase (PC), acetyl CoA carboxylase 1 and 2 (ACC1, ACC2), propionyl CoA carboxylase (PCC), and methylcrotonyl CoA carboxylase (MCC). These carboxylases are essential for neurological health due to their essential role in carbohydrate, lipid and branched-chain amino acid metabolism (8). Functional and structural changes in the brain during biotin deficiency may contribute to the mechanism of systemic and neurological manifestations of biotin deficiency, including seizures that are poorly controlled by AED, lactic acidosis and hyperammonemia (9,10).
The mechanisms underlying CBZ-induced biotin deficiency are not well understood, although several hypotheses have been proposed and supported (6,7,11). Biotin transport is competitively inhibited by CBZ and primidone in purified brush border membrane vesicles isolated from human intestine (11). CBZ, primidone and biotin share a ureido moiety, suggesting that this may be an important recognition motif for the transporter (11). Another potential mechanism of CBZ-induced biotin deficiency includes accelerated catabolism of biotin. Both adults and children undergoing long-term AED therapy exhibit accelerated biotin catabolism to its inactive catabolites bisnorbiotin (BNB) and biotin sulfoxide (BSO) (6,7). CBZ metabolism in humans and rats is similar in that the same active and inactive catabolites are produced; however, different cytochrome P450 enzymes are activated between species (12).
We demonstrated previously that dietary CBZ administration to rats decreases the abundance of both brain and hepatic biotinylated PC (13). We also observed increased brain lactate concentration, which could be due to decreased function of brain PC. The mechanism by which CBZ decreased the abundance of the biotinylated and, therefore, active PC is unknown and was investigated in the current study. Decreased abundance of biotinylated PC could be due to either decreased expression of the total protein or decreased abundance of the holocarboxylase form of the enzyme. This study examined PC protein abundance and the proportions of apolipoprotein-PC and biotinylated PC using an in vitro biotinylation technique as well as expression of PC mRNA after dietary CBZ administration to rats.
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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 (14) was obtained from Research Diets (New Brunswick, NJ). 5-Ethyl-5-p-tolylbarbituric acid, CBZ, CBZ 10,11-epoxide, D-biotin, protease inhibitor cocktail, [14C]NaHCO3 and o-phenylenediamine dihydrochloride were purchased from Sigma Chemical (St. Louis, MO); avidin-horseradish peroxidase and avidin-alkaline phosphatase were purchased from Pierce Chemical (Birmingham, AL); 96-well microtiter plates (Nunc Maxisorb), ScintiSafe liquid scintillation cocktail and bovine serum albumin (BSA) were purchased from Fisher Scientific (Pittsburgh, PA). Enhanced chemifluorescence reagent was purchased from Amersham-Pharmacia (Picastaway, NJ). Biotinylated BSA, and Avidin-AlexaFluor 430 conjugate were synthesized as previously described (15).
Animals and dietary treatments.
Male Sprague-Dawley rats (n = 11), 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 acclimatized by feeding a powdered egg-white based modification of the AIN76a diet containing 0.06 mg biotin/kg diet for 5 d to standardize their biotin status as previously described (15). This modified AIN76a diet contained avidin, a component of egg-white protein, that binds 1.44 mg biotin/kg diet and renders 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 (15) and was confirmed to be 0.06 mg biotin/kg diet. After 5 d of acclimatization, the rats were randomly assigned to 2 groups: one group received 0 g CBZ/kg diet (n = 5) and one group received 3.75 g CBZ/kg diet (n = 6) fed for 28 d. Food intake and body weights were recorded daily for all rats. All procedures were approved by the University of Florida Animal Care and Use Committee.
Sample preparation.
On d 28, rats were anesthetized under halothane and killed via cardiac puncture and exsanguination. Whole blood was allowed to coagulate for 30 min and was then centrifuged at 13,000 x g for 5 min to separate serum. Whole brain was removed and minced before homogenizing 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 10 sections and all samples were immediately frozen in liquid nitrogen and stored at -80°C until further use for enzymatic activity assays or mRNA isolation. For liver protein extract preparation, a frozen liver portion was thawed and homogenized in 10 volumes of ice-cold HEM. A portion of each homogenate was saved for enzyme biotinylation assays; the remainder was centrifuged at 200,000 x g for 30 min at 4°C to collect the soluble fraction for determination of biotin and biotin metabolites. All homogenized samples were immediately frozen in liquid nitrogen and stored at -80°C until assayed.
Pyruvate carboxylase activity assay.
PC activity in brain and liver was as described by Suormala et al. (16). The final reaction mixture volume of 0.1 mL consisted of 100 mmol/L Tris HCl, pH 8.0, 3.8 mmol/L MgCl2, 3.14 mmol/L ATP, 0.32 mmol/L acetyl CoA, 0.5% Triton X-100, freshly prepared 7.5 mmol/L pyruvate and 4 mmol/L [14C]NaHCO3 (specific activity 40.7 MBq/mmol). Background activity was determined by omitting pyruvate from the reaction mixture. Aliquots of the crude homogenate (0.1 mg) were added and allowed to incubate at 37°C for 15 min. PC activity was determined to be linear up to at least 25 min. 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 resuspend and wash the protein pellet. The pellet was centrifuged at 13,000 x g for 5 min and the supernatant added to the corresponding scintillation vial. 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 activities were expressed as nmol oxaloacetate formed/(mg protein · min).
Detection of biotinylated biotin-dependent carboxylases.
The five biotin-dependent carboxylases, acetyl CoA carboxylase isoforms 1 and 2 (ACC1, ACC2), pyruvate carboxylase (PC), propionyl CoA carboxylase (PCC) and methylcrotonyl CoA carboxylase (MCC) were detected using the avidin blotting technique described previously with slight modifications (15). Because of their similar molecular weights, PCC and MCC are not 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).
In vitro biotinylation.
Total liver PC protein was determined as described by Rodriguez-Melendez et al. (17). Briefly, liver homogenate (500 µg protein) was added to 450 µL of a master mix providing a final concentration of 60 mmol/L Tris HCl, pH 7.5, 0.82 mmol/L biotin, 0.1 mmol/L EDTA, 0.6 g/L BSA, 3 mmol/L reduced glutathione, 8 mmol/L MgCl2 and 10 mmol/L ATP. The reaction mixture was incubated for 6 h at 37°C. At 2 and 4 h of incubation, an additional 26.75 µL of a solution containing 10 mmol/L ATP and 8 mmol/L MgCl2 was added. Finally, the reaction was terminated by adding 500 µL sample dilution buffer [0.375 mol/L Tris-HCl, pH 6.8, 2.3 g/L SDS, 350 mL/L glycerol, 0.035 g/L bromophenol blue and 1.43 mol/L ß-mercaptoethanol]. A portion of each sample (40 µg protein) was loaded and resolved on a 10% SDS-PAGE gel, transferred to polyvinylidene difluoride membrane and detected by avidin-Western blotting as previously described (14).
Measurement of biotin, BSO, BNB and biocytin.
The measurement of biotin and its metabolites in serum, liver and brain was performed using a coupled HPLC/competitive binding assay described previously (15,18).
Measurement of carbamazepine.
Serum, liver, brain and dietary CBZ were measured using a method previously described (19) with slight modifications (13). For determination of CBZ in the diet, 1 g diet powder was mixed with 5 mL acetone containing 10 mg 5-ethyl-5-p-tolylbarbituric acid/L and blended with a vortex mixer for 10–15 min. The mixture was centrifuged at 13,000 x g for 10 min and the soluble fraction was recovered for analysis. For serum, an equal volume of acetone containing 10 mg/L tolylbarbituric acid was added and vortexed followed by centrifugation at 13,000 x g for 5 min. Tissues were prepared by homogenizing in 10 volumes of ice-cold homogenization buffer as described above. After centrifuging 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/L tolylbarbituric acid and centrifuged at 13,000 x g for 5 min at room temperature. All soluble fractions were mixed with two volumes of dichloromethane and blended with a vortex mixer. The aqueous layer was removed and the organic layer was dried at 65°C and resuspended in methanol. All samples were filtered and analyzed using HPLC (13).
RNA isolation and northern blotting.
Frozen liver was homogenized in Trizol reagent (Invitrogen Life Technologies, Carlsbad, CA) and RNA was isolated as directed by the manufacturer. RNA was quantified by absorbance at 260 nm and purity assessed by calculation of the ratio of the absorbance at 260 nm to absorbance at 280 nm. RNA integrity was analyzed by 1.2% agarose gel electrophoresis in 1 x TBE (89 mmol/L Tris base, 89 mmol/L boric acid, 2 mmol/L EDTA) with ethidium bromide staining (20).
After electrophoresis, RNA was transferred to a nylon membrane (Millipore, Bedford, MD) using an overnight downward capillary transfer technique (20). The nucleic acids were cross-linked to the membrane using 160,000 µJ short wave UV light and allowed to dry completely before probing. The random priming labeling kit (Gibco BRL, Gaithersburg, MD) was used to label a rat PC cDNA probe with 32P. The PC cDNA probe was hybridized to the homologous RNA and to normalize for lane-to-lane variation, and a mouse ß-actin cDNA probe was used to detect ß-actin mRNA. Both PC and ß-actin were detected by phosphor imaging using a STORM840 fluorescent imager (STORM, Sunnyvale, CA) following the manufacturer’s instructions. Densitometry of the resulting image was performed using ImageQuant software (Amersham Pharmacia).
Real-time reverse transcriptase PCR conditions.
Using cDNA sequences for PC retrieved from GenBank, real time PCR primers and TaqMan probe were designed using Primer Express software version 1.0 (PE Applied Biosystems, Foster City, CA). The primers and TaqMan probe for PC were synthesized by Keystone Labs (Biosource International, Camarillo, CA) with a FAM reporter dye and quencher BHQ1 (Table 1). The primers and TaqMan probe for 18S rRNA gene were purchased from PE Applied Biosystems and used as the endogenous control for RNA.
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All assays were performed using one-step RT-PCR reagents and a GeneAmp 5700 Sequence Detection System (PE Applied Biosystems) in a 25 µL reaction volume as employed by Moore et al. (21). RT-PCR conditions were as follows: 30 min at 48°C, 10 min at 95°C, 50 cycles of 15 s at 95°C and 1 min at 60°C. Relative quantification was determined from a 3–4 log range standard curve generated from serially diluted RNA to final concentrations of 10, 1, 0.1, 0.01 and 0.001 ng/µL. Quantification was performed by interpolation using a standard regression curve of threshold cycle (Ct) values generated from RNA samples of these known concentrations. Total RNA (1 ng) isolated from individual rats was used for these experiments and all samples were run in duplicate. The reaction mixture contained 900 nmol/L each of the forward and reverse primers and 250 nmol/L of PC TaqMan probe, whereas the 18S rRNA TaqMan assay utilized 50 nmol/L forward and reverse primers and 50 nmol/L TaqMan probe. To ensure that the total RNA samples were not contaminated with DNA, RNA samples with no reverse transcriptase added were run.
Statistical analysis.
Results are expressed as mean ± SD. The significance of differences (P < 0.05) was tested by Student’s t test. 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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Direct analysis of the diet by HPLC confirmed the intended concentration of 3.4 g CBZ/kg. Food intake and body weight gain did not differ between treatment groups over the 28-d experiment (data not shown). At the end of the study, serum CBZ concentration of the CBZ-treated group was 11 ± 7.1 µmol/L, whereas liver and brain CBZ concentrations were 80 ± 4.0 and 38 ± 2.1 nmol/g tissue, respectively.
After consuming the 3.4 g CBZ/kg diet for 28 d, the rats had a higher concentration of lactic acid in the brain than control rats (10 ± 2.8 vs. 6.2 ± 2.1 µmol/g, P < 0.05). Serum concentrations of lactic acid at 28 d did not differ between rats consuming the 3.4 g CBZ/kg diet (6.3 ± 1.0 mmol/L) and those consuming the control diet (7.2 ± 2.8 mmol/L).
The administration of 3.4 g CBZ/kg diet for 28-d did not affect serum, liver or brain biotin, BSO or BNB (data not shown). The distribution of biotin and metabolites in brain, liver and serum was similar to results from our previous studies (13). Only brain biocytin was elevated in rats consuming 3.4 g CBZ/kg diet compared with controls (3.6 ± 1.0 and 1.2 ± 0.26 pmol/g tissue, respectively, P < 0.05).
Effect of CBZ administration on PC biotinylation, activity, and protein and mRNA expression.
The relative abundance of hepatic biotinylated PC was 43% lower in rats consuming the 3.4 g CBZ/kg diet than in controls (P < 0.05) (Fig. 1A). Brain biotinylated PC was 29% lower (P < 0.05) in rats consuming the 3.4 g CBZ/kg diet than in controls (Fig. 1A). There was no difference in the relative abundance of biotinylated MCC, PCC, ACC1 or ACC2 in either brain or liver of rats consuming 3.4 g CBZ/kg diet compared with controls (data not shown). Hepatic PC specific enzymatic activity was 30% lower in rats consuming the 3.4 g CBZ/kg diet than in controls but brain PC activity was 175% higher in this group (P < 0.05) than in controls (Fig. 1B).
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43%) in rats consuming the 3.4 g CBZ/kg diet than in controls (Fig. 2A). At the RNA level, after normalizing the hepatic PC mRNA with ß-actin, PC mRNA in the drug treated group tended to be lower than controls (Fig. 3).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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5 µmol/L (13), which is less than the therapeutic range for both rats and humans, typically 17–51 µmol/L (23,24). In the present experiment, we sought to increase the oral CBZ intake to result in a serum CBZ level more closely approximating the therapeutic range. Serum CBZ was 12 µmol/L, which is still slightly below the therapeutic range for the treatment of epilepsy; thus, these results could be interpreted as conservative in relation to what could occur at higher CBZ doses. We found previously that oral CBZ administration to rats yields decreased hepatic abundance of biotinylated PC. Because the relative abundance of biotinylated PC depicts the holocarboxylase form of the enzyme and not the apocarboxylase, we wanted to determine whether the decrease was due to reduction in the biotinylation (therefore the same concentration of total protein) or decreased PC protein concentration. By biotinylating all of the available apocarboxylase form of the enzyme in vitro and then detecting by avidin blotting (17), we determined that there was a change in total PC protein. The decrease in PC protein was confirmed by Western blot using a polyclonal PC antibody (data not shown). To determine whether the decreased protein level was due to protein degradation or transcriptional regulation, PC mRNA was quantified using both Northern blotting and real-time PCR. After normalizing PC mRNA for ß-actin mRNA, there were no differences between the drug-treated group and controls as detected by Northern blotting. Real-time PCR, however, showed that CBZ induced a significant 35% decrease in hepatic PC mRNA in the drug-treated group after normalizing for 18 S rRNA. Two factors are likely involved that contribute to the different results between methods, including the possible expression differences in ß-actin mRNA and 18 S rRNA between drug and control groups as well as the increased sensitivity of real-time PCR. It is possible that CBZ alters ß-actin mRNA as well as PC mRNA. It is also true that normalizing for 18 S should be more accurate because this accounts for most of the RNA measured by an absorbance reading at 260 nm, and from that number, equal amounts were loaded in each reaction. The greater reproducibility and sensitivity of real-time PCR gives credence to the fact that hepatic PC mRNA was significantly lower in the drug-treated group than in controls. The 35% decrease in PC mRNA was accompanied by approximately the same magnitude of decreases found for hepatic PC protein, biotinylation, and activity, which suggests that the decreased mRNA expression was responsible for the lower PC protein and activity. Furthermore, the decreased PC protein provides an explanation for the decreased detection of biotinylated PC and PC specific activity observed in earlier studies (13). Although the present study utilized only one dose of CBZ, we predict that CBZ decreased PC protein and mRNA expression in a dose-dependent manner on the basis of results from our previous study in which we found that CBZ decreased biotinylated PC in a dose-dependent manner (13).
The relative abundance of brain biotinylated PC was also reduced, but not to the extent seen in the liver (29% lower in brain compared with 43% in liver). This is consistent with a protective mechanism in the brain to preferentially maintain biotin status and biotin-dependent enzyme function compared with other tissues during periods of biotin deficiency (25–27). Biotinidase activity has also been found in previous studies to be lower in the brain than in other tissues, which also suggests a slower turnover of biotinylated proteins in the brain (28). This is supportive of our different results between brain and liver biocytin concentration and biotinylated PC.
The dietary administration of CBZ increased brain lactate but did not change serum lactate concentration. Elevated lactate in urine of patients undergoing long-term AED therapy is observed clinically and may be due to the same mechanism as the elevated brain lactate. Elevated lactate in the brain is associated with selective neuronal damage in cerebral ischemia and impaired neurological function (29–32), but more recently it has been argued that lactate may play an important role in nourishing oligodendrocytes and neurons (33–35). Whether elevated lactate concentration is detrimental to the brain is debatable, but it should be given some consideration because lactate does not cross the blood brain barrier easily and it can act as a toxin in other tissues (36,37). One possible mechanism to explain the elevated lactate is a reduction in PC mRNA leading to decreased PC protein synthesis and decreased PC activity. PC catalyzes the carboxylation of pyruvate to form oxaloacetate and, as seen in PC deficiencies, decreased PC activity could lead to elevated lactate because pyruvate can build up and be shunted to alternate pathways, including lactate (38,39). Although we observed a decrease in hepatic mRNA, PC protein and PC activity, there was a 175% increase in brain PC activity in the drug-treated group compared with controls. This was not expected because the relative abundance of brain biotinylated PC, which is the active form of the enzyme, was 30% lower. Although the mechanism underlying this discrepancy is not understood at this time, allosteric activators of PC may be responsible for the increased brain PC activity and warrant further study. Even though CBZ increased brain PC activity as measured in vitro and we would not expect lactate accumulation in compartments with increased PC activity, lactate could be formed in other tissues and transported into the brain across the blood brain barrier by the monocarboxylate transporter MCT1 that is present on vascular endothelial cells (40). In contrast, lactate accumulation in the brain that is observed in these studies may not be related to PC function per se. We are presently investigating this in our laboratory.
Although it is established clinically that chronic treatment with AED including CBZ is associated with biotin deficiency, the effect on tissue biotin and biotin-dependent enzymes involved in carbohydrate, lipid and protein metabolism is less understood. Metabolic changes of biotin in the brain are of particular importance because alterations of brain biotin status and subsequent loss of function of biotin-dependent enzymes can contribute to impaired neurological health. The potential protective role of biotin supplementation during CBZ administration is an important question that remains to be answered and is currently under investigation in our laboratory. This characterization will have important clinical relevance because biotin may have future use in the medical management of epilepsy.
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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; Ct, threshold cycle; MCC, methylcrotonyl CoA carboxylase; PC, pyruvate carboxylase; PCC, propionyl CoA carboxylase; TCA, trichloroacetic acid.
Manuscript received 21 February 2003. Initial review completed 9 April 2003. Revision accepted 25 April 2003.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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