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PubMedDate not supplied

Nutritional and metabolic characterization of a thiamine-deficient rat model.

The effects of a thiamine-deficient diet on plasma and tissue vitamin concentrations and on whole-body glucose metabolism were assessed. Male Sprague-Dawley rats (175 to 200 g body weight) fed a thiamine-deficient (TD) or nutritionally complete purified diet were used for plasma thiamine mononitrate and monophosphate and for red blood cell and tissue thiamine pyrophosphate (TPP) determinations weekly for up to 5 weeks. Additional rats were used for assessment of basal glucose kinetics by using a primed constant infusion of [3-3H]glucose. Plasma thiamine mononitrate levels decreased 60% at 1 week and were undetectable after 5 weeks on the diet. Plasma thiamine monophosphate decreased 80% after 1 week on the TD diet, and levels were undetectable after 4 weeks on the diet. Red blood cell TPP in the TD group decreased progressively with time: 54% at 1 week, 86% at 3 weeks, and 92% at 5 weeks. At 1 and 4 weeks, the decrease in tissue TPP was significant in the liver (65% and 89%, respectively), gut (52% and 94%, respectively), spleen (40% and 60%, respectively), and skeletal muscle (37% and 76%, respectively), with the brain (7% and 84%, respectively) showing the slowest initial rate of depletion. The TD diet did not alter plasma glucose concentrations, but it increased plasma lactate by 75% and plasma pyruvate by 50% to 75%. Rates of hepatic glucose production and peripheral glucose utilization were not different between the control and TD rats at 2 weeks, but they were 25% higher in the TD rats after 6 weeks on the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Thiamine deficiency in hematologic malignant tumors.

The case is reported of a patient with acute myeloid leukemia with severe right-sided congestive heart failure that responded to treatment with thiamine. Leukocytes cells contain relatively high concentrations of thiamine-dependent enzymes compared with erythrocytes. Because no other cause could be found, it was postulated that consumption of thiamine by blast cells was responsible for the deficiency. After studying this patient, the thiamine pyrophosphate (TPP) effect was measured in five other consecutive patients with fast-growing hematologic malignant tumors. In two patients, the TPP effect was elevated slightly, but another patient had a definite thiamine deficiency with severe cardiac failure. It is suggested that the clinician be alert for this underdiagnosed potentially fatal but easily treatable deficiency in nonalcoholic patients with fast-growing hematologic cancers.

Adult↗

PubMed1983

The effect of nitrofurazone on the thiamin status of chickens.

Nitrofurazone, given orally at doses of 10 and 20 mg/kg for seven days, decreased the activity of erythrocyte transketolase (TK) and increased the activation of TK by thiamin pyrophosphate (TPP effect %). Nitrofurazone also decreased the feed intake and growth of the chickens, and increased the concentrations of lactate and pyruvate of their blood. It was concluded that nitrofurazone has induced thiamin deficiency in the treated birds. Pair-feeding experiments showed that the decreased growth was due to anorexia, and that the effects produced by nitrofurazone treatment on the thiamin status were attributable to the drug, per se, and not to anorexia. Thiamin (100 micrograms/kg, injected subcutaneously), when given concomitantly with nitrofurazone, was effective in preventing the development of thiamin deficiency.

Animals↗

PubMed2002

Comparative genomics of thiamin biosynthesis in procaryotes. New genes and regulatory mechanisms.

Vitamin B(1) in its active form thiamin pyrophosphate is an essential coenzyme that is synthesized by coupling of pyrimidine (hydroxymethylpyrimidine; HMP) and thiazole (hydroxyethylthiazole) moieties in bacteria. Using comparative analysis of genes, operons, and regulatory elements, we describe the thiamin biosynthetic pathway in available bacterial genomes. The previously detected thiamin-regulatory element, thi box (Miranda-Rios, J., Navarro, M., and Soberon, M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 9736-9741), was extended, resulting in a new, highly conserved RNA secondary structure, the THI element, which is widely distributed in eubacteria and also occurs in some archaea. Search for THI elements and analysis of operon structures identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various prokaryotic organisms. In particular, we assign the thiamin transporter function to yuaJ in the Bacillus/Clostridium group and the HMP transporter function to an ABC transporter thiXYZ in some proteobacteria and firmicutes. By analogy to the model of regulation of the riboflavin biosynthesis, we suggest thiamin-mediated regulation based on formation of alternative RNA structures involving the THI element. Either transcriptional or translational attenuation mechanism may operate in different taxonomic groups, dependent on the existence of putative hairpins that either act as transcriptional terminators or sequester translation initiation sites. Based on analysis of co-occurrence of the thiamin biosynthetic genes in complete genomes, we predict that eubacteria, archaea, and eukaryota have different pathways for the HMP and hydroxyethylthiazole biosynthesis.

Base Sequence↗

PubMed2006

Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo.

We previously demonstrated that copper facilitated the formation of reactive oxygen species, and inhibited pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in animal models of Wilson's disease in vivo. However, direct Cu(2+) toxicity has only been demonstrated for Wilson's disease. We now hypothesize that inhibition of these mitochondrial dehydrogenases might also contribute to many other injuries and disorders that are reactive oxygen species-mediated. We have modeled reactive oxygen species-mediated injuries using inducers of reactive oxygen species such as hydrogen peroxide, ethacrynic acid or menadione, or another redox active metal (Cd(2+)). Here we demonstrated that these toxic exposures were accompanied by an early marked reduction in both pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activities, followed by a decrease in neuronal mitochondrial transmembrane potential and ATP, prior to murine cortical neuronal death. Thiamine (6 mM), and dihydrolipoic acid (50 microM), required cofactors for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (thiamine as thiamine pyrophosphate), attenuated the reactive oxygen species-induced reductions in these enzyme activities, as well as subsequent loss of mitochondrial transmembrane potential and ATP, and neuronal death. We next tested the effect of thiamine supplementation on an in vivo model of reactive oxygen species-mediated injury, transient middle cerebral artery occlusion, and reperfusion in rats. Oral or i.p. thiamine administration reduced the middle cerebral artery occlusion-induced infarct. These data suggest that reactive oxygen species-induced neuronal death may be caused in part by reactive oxygen species-mediated inhibition of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in vivo, and that thiamine or dihydrolipoic acid may constitute potential therapeutic agents not just against Cu(2+) neurotoxicity, but may reduce neuronal degeneration in the broader range of diseases mediated by free radical stress.

Adenosine Triphosphate↗

PubMed1982

[Disorders of amino acid metabolism in a patient with identified thiamine deficiency].

Report on a serious disturbance of amino-acid metabolism in a 56 year old male patient suffering from thiamine-(vitamin B-1) deficiency, as proven by clinical history and examination and by laboratory data. In comparison with a group of 75 normal male persons also evaluated by the same laboratory this patient--while thiamine deficient--had markedly elevated serum concentrations outside the physiologic range of glutamic acid, glutamine, proline, citrulline, ornithine, histidine, lysine, phenylalanine, tyrosine and leucine, whereas his serum concentrations of taurine, serine and isoleucine were comparably definitely lowered. Following six to seven days of daily i.m. injections of 200 mg of thiamine each, this imbalance of amino-acid homeostasis disappeared except for that of taurine and--questionably--that of phenylalanine. In view of the absence of other exogenous or endogenous potential causes for this, it must be presumed that the thiamine-pyrophosphate deficiency caused the imbalance of amino-acid metabolism by consecutively disturbing the function of the alpha-ketoglutarate-, pyruvate- and p-hydroxy-phenylpyruvate- decarboxylase chains respectively. Possible connections between thiamine-deficiency and lowered serum concentrations of serine, taurine and isoleucine are being discussed.

Amino Acids↗

PubMed2000

Changes in thiamin, riboflavin, niacin, beta-carotene, vitamins, C, A, D and E status of French Elderly Subjects during the first year of institutionalization.

Vitamin status was assessed in 26 recently institutionalized elderly subjects by combining dietary and biochemical measurements of thiamin, riboflavin, niacin, beta-carotene, vitamins C, A, D and E at admission (P1), and 1.5 (P2), 3.0 (P3), 4.5 (P4), 6.0 (P5), 12 (P6) months later. At admission, except for vitamin A, mean vitamin intakes were lower than the 1992 French Recommended Dietary Allowance. Thiamin, vitamins C, A and E status seemed nearly satisfactory as less than one-fourth of the population sample had blood values lower than the cut-off point for thiamin (erythrocyte thiamin pyrophosphate < 0.17 mumol/l), vitamin A (serum retinol < 1.05 mumol/l), vitamin C (serum vitamin C < 11.3 mumol/l) and vitamin E (serum alpha-tocopherol < 9.3 mumol/l) or higher than the cut-off point for thiamin (erythrocyte transketolase activity coefficient > 1.19). Almost half of the subjects for riboflavin, and almost all non supplemented subjects for vitamin D were in risk of vitamin deficiency (46% had an erythrocyte glutathione reductase activity coefficient > 1.19 and 72% had a plasma 25(OH)D3 < 25 nmol/l). During the study, vitamins status remained unchanged for riboflavin, niacin, vitamins A, D and E, improved for vitamin C (P = 0.004) or impaired for thiamin (P = 0.008). Thus, institutionalization seemed to have no effect on riboflavin, niacin, vitamins A, D and E status and a slight effect on thiamin and vitamin C status.

Aged↗

PubMed1988

Thiamine pyrophosphatase (nucleoside diphosphatase) in the Golgi apparatus is distinct from microsomal nucleoside diphosphatase.

The properties of thiamine pyrophosphatase in the Golgi apparatus of rat liver were studied. Thiamine pyrophosphatase in an extract of the Golgi apparatus was separated into 6 bands of between pH 5.4 and 6.3 by isoelectric focusing on polyacrylamide gel. On the gels all these subforms catalyzed the hydrolyses of GDP, IDP, UDP, and CDP as well as that of thiamine pyrophosphate. The characteristics resembled those of Type B nucleoside diphosphatase of rat brain, though the enzyme did not have 3 subforms of Type B nucleoside diphosphatase in the higher pH region on isoelectric focusing. Thiamine pyrophosphatase of the Golgi apparatus was separated from microsomal nucleoside diphosphatase by DEAE-cellulose column chromatography. The properties of the enzyme were quite similar to those of Type B nucleoside diphosphatase with respect to its substrate specificity, optimum pH for activity, and inhibition by ATP. These findings suggest that thiamine pyrophosphatase in the Golgi apparatus is different from microsomal nucleoside diphosphatase and that it might be basically the same enzyme as Type B nucleoside diphosphatase except for different extents of modification.

Acid Anhydride Hydrolases↗

PubMed1989

Effects of thiamine deficiency on brain metabolism: implications for the pathogenesis of the Wernicke-Korsakoff syndrome.

Chronic alcoholism results in thiamine deficiency as a consequence of inadequate dietary intake and of impaired absorption of the vitamin. In addition, there is evidence to suggest that alcohol reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in brain. TPP is a cofactor for the pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase (alpha KGDH) and transketolase (TK), three enzymes involved in cerebral glucose and energy metabolism. Pyrithiamine-induced thiamine deficiency in the rat results in early, selective, reversible reductions of alpha KGDH in brain; PDHC activities are unaffected. Reductions of alpha KGDH are accompanied by decreased aspartate, glutamate and GABA and by concomitantly increased alanine in the brain of thiamine-deficient animals. It is suggested that decreased alpha KGDH, rather than decreased PDHC constitutes 'the biochemical lesion' in thiamine deficiency encephalopathy first enunciated by Peters in the 1930s. If sufficiently prolonged and severe, thiamine deficiency results in brain cell death. Possible mechanisms involved include compromised cerebral energy metabolism and focal accumulation of lactate, both of which could result from decreased activities of alpha KGDH. In addition, it is proposed that brain cell death in severe thiamine deficiency may result from excessive release of excitotoxic amino acids. Comparable mechanisms could be involved in the cell death and in the pathogenesis of the thiamine-unresponsive symptoms of the Wernicke-Korsakoff Syndrome in humans.

Alcohol Amnestic Disorder↗

PubMed2002

Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells.

Although the reduced folate carrier RFC1 and the thiamine transporters THTR-1 and THTR-2 share approximately 40% of their identity in protein sequence, RFC1 does not transport thiamine and THTR-1 and THTR-2 do not transport folates. In the present study, we demonstrate that transport of thiamine monophosphate (TMP), an important thiamine metabolite present in plasma and cerebrospinal fluid, is mediated by RFC1 in L1210 murine leukemia cells. Transport of TMP was augmented by a factor of five in cells (R16) that overexpress RFC1 and was markedly inhibited by methotrexate, an RFC1 substrate, but not by thiamine. At a near-physiological concentration (50 nM), TMP influx mediated by RFC1 in wild-type L1210 cells was approximately 50% of thiamine influx mediated by thiamine transporter(s). Within 1 min, the majority of TMP transported into R16 cells was hydrolyzed to thiamine with a component metabolized to thiamine pyrophosphate, the active enzyme cofactor. These data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia.

Animals↗

PubMed1990

Clinical and biochemical alterations in calves with nutritionally induced polioencephalomalacia.

Polioencephalomalacia (PEM) was induced in calves by feeding a semipurified, low-roughage diet of variable copper and molybdenum composition. Two formulations resulting in Cu-insufficient and Cu-sufficient forms of the diet were fed (n = 10 and 4 calves, respectively); both diets induced PEM. Clinical signs of disease developed as early as 15 days after transition to the experimental diets and included impaired vision, decreased response to external stimuli, and abnormal gait. Grossly evident cerebrocortical lesions consisted of laminar areas of cavitation and/or autofluorescence seen under UV illumination. Hepatic Cu concentration was decreased in calves fed the Cu-insufficient diet, but not below normal range. During the course of feeding either diet, rumen pH decreased, rumen volatile fatty acid concentrations increased, rumen and blood lactic acid concentrations increased, and rumen and plasma thiamine concentrations increased. The thiamine pyrophosphate effect on erythrocyte transketolase activity was unaltered in calves of either diet group. This nutritionally induced form of PEM does not appear to be related to Cu deficiency or reduction in plasma or rumen thiamine concentration.

Animals↗

PubMed2006

Recent progress in understanding thiamin biosynthesis and its genetic regulation in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae is able to synthesize thiamin pyrophosphate (TPP) de novo, which involves the independent formation of two ring structures, 2-methyl-4-amino-5-hydroxymethylpyrimidine and 4-methyl-5-beta-hydroxyethylthiazole, in the early steps. In addition, this organism can efficiently utilize thiamin from the extracellular environment to produce TPP. Nineteen genes involved in the synthesis of TPP and the utilization of thiamin (THI genes) have been identified, and the function of several THI genes has been elucidated. All THI genes participating in the synthesis of the pyrimidine unit belong to multigene families. It is also intriguing that some thiamin biosynthetic proteins are composed of two distinct domains or form an enzyme complex. The expression of THI genes is coordinately induced in response to thiamin starvation. It is likely that the induction of THI genes is activated by a positive regulatory factor complex and that the protein-protein interaction among the factors is disturbed by TPP. Thiamin-hyperproducing yeast and fermented food containing a high content of thiamin are expected to be available in the future based on the progress in understanding thiamin biosynthesis and its genetic regulation in S. cerevisiae.

Gene Expression Regulation, Fungal↗

PubMed2006

The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure.

OBJECTIVES: The purpose of this study was to determine the prevalence of thiamin deficiency (TD) in a cross section of hospitalized congestive heart failure (CHF) patients and to investigate factors that contribute to its development. BACKGROUND: Thiamin deficiency manifests as symptoms of CHF and, therefore, may worsen existing heart failure. Congestive heart failure patients may be at increased risk for TD as a result of diuretic-induced urine thiamin excretion, disease severity, malnutrition, and advanced age. METHODS: Erythrocyte thiamin pyrophosphate concentrations, using high-performance liquid chromatography, were measured in 100 CHF patients and compared to 50 control subjects. Variables including diuretics (type and dose), left ventricle dysfunction, New York Heart Association functional classification, creatinine clearance, thiamin intake (diet and supplements), malnutrition, appetite ratings, and age were related to TD using univariate statistics and multiple logistic regression analysis. RESULTS: Thiamin deficiency was more prevalent in CHF patients (33%) compared to control subjects (12%) (p = 0.007). Thiamin deficiency was related to urine thiamin loss (p = 0.03), non-use of thiamin-containing supplements (p = 0.06), and preserved renal function (p = 0.05). Increased urinary thiamin loss (mug/g creatinine) was found to be the only significant positive predictor of thiamin status on multiple logistic regression analysis (p = 0.03). CONCLUSIONS: One-third of hospitalized CHF patients were TD. In contrast to previous studies, increased urinary losses of thiamin were predictive of improved thiamin status. Thiamin supplementation may be protective against TD in the clinical setting. Future studies are warranted to determine if thiamin supplementation improves thiamin status and disease severity in CHF patients.

Aged↗

PubMed1995

Intestinal alkaline phosphatase can transphosphorylate thiamin to thiamin monophosphate during intestinal transport in the rat.

Intestinal alkaline phosphatase (IAP) purified from calf intestine and IAP present in the brush border membrane of rat small intestine effectively transphosphorylated thiamin (T) to thiamin monophosphate (TMP) using Na2-beta-glycerophosphate or Na2-creatine phosphate as phosphate donors at pH 8.5. TMP production in the brush border membrane was very small and corresponded to 0.001-0.01 percent of the total inorganic phosphate simultaneously released by the enzyme activity. This reaction, however, could account for TMP formation independently from that much more important due to the hydrolysis of thiamin pyrophosphate during T intestinal absorption.

Alkaline Phosphatase↗

PubMed2000

Lesions in gshA (Encoding gamma-L-glutamyl-L-cysteine synthetase) prevent aerobic synthesis of thiamine in Salmonella enterica serovar typhimurium LT2.

Thiamine pyrophosphate is an essential cofactor that is synthesized de novo in Salmonella enterica serovar Typhimurium and other bacteria. In addition to genes encoding enzymes in the biosynthetic pathway, mutations in other metabolic loci have been shown to prevent thiamine synthesis. The latter loci identify the integration of the thiamine biosynthetic pathway with other metabolic processes and can be uncovered when thiamine biosynthesis is challenged. Mutations in gshA, encoding gamma-L-glutamyl-L-cysteine synthetase, prevent the synthesis of glutathione, the major free thiol in the cell, and are shown here to result in a thiamine auxotrophy in some of the strains tested, including S. enterica LT2. Phenotypic characterization of the gshA mutants indicated they were similar enough to apbC and apbE mutants to warrant the definition of a class of mutants unified by (i) a requirement for both the hydroxymethyl pyrimidine (HMP) and thiazole (THZ) moiety of thiamine, (ii) the ability of L-tryosine to satisfy the THZ requirement, (iii) suppression of the thiamine requirement by anaerobic growth, and (iv) suppression by a second-site mutation at a single locus. Genetic data indicated that a defective ThiH generates the THZ requirement in these strains, and we suggest this defect is due to a reduced ability to repair a critical [Fe-S] cluster.

Aconitate Hydratase↗

PubMed1980

Chlormethiazole and utilization of vitamin B1 in chronic alcoholics.

Blood vitamin B1 status as reflected by erythrocyte transketolase activation tests has been assessed in 12 chronic alcoholic (M = 8; F = 4; mean age +/- 53.4 +/- 12.9) both before and after treatment with chlormethiazole and parenteral polyvitamins including thiamine hydrochloride. 7 out of 12 patients (58.3%) were found to be deficient before treatment but all returned to normal after treatment. Mean +/- SD, of alpha ETK improved pre-treatment level of 1.174 +/- 0.135 to 1.009 +/- 0.009 after treatment with thiamine. Chlormethiazole did not seem to interfere with the utilization of thiamine. It is therefore concluded, that though structurally related to the thiazole nucleus of thiamine, chlormethiazole, like thiamine antagonists, does not antagonize the effect of the co-enzyme - thiamine pyrophosphate at the receptor sites on the apo-enzyme - transketolase.

Adult↗

PubMed1998

The apbE gene encodes a lipoprotein involved in thiamine synthesis in Salmonella typhimurium.

Thiamine pyrophosphate is an essential cofactor that is synthesized de novo in Salmonella typhimurium. The biochemical steps and gene products involved in the conversion of aminoimidazole ribotide (AIR), a purine intermediate, to the 4-amino-5-hydroxymethyl-2-methyl pyrimidine (HMP) moiety of thiamine have yet to be elucidated. We have isolated mutations in a new locus (Escherichia coli open reading frame designation yojK) at 49 min on the S. typhimurium chromosome. Two significant phenotypes associated with lesions in this locus (apbE) were identified. First, apbE purF double mutants require thiamine, specifically the HMP moiety. Second, in the presence of adenine, apbE single mutants require thiamine, specifically both the HMP and the thiazole moieties. Together, the phenotypes associated with apbE mutants suggest that flux through the purine pathway has a role in regulating synthesis of the thiazole moiety of thiamine and are consistent with ApbE being involved in the conversion of AIR to HMP. The product of the apbE gene was found to be a 36-kDa membrane-associated lipoprotein, making it the second membrane protein implicated in thiamine synthesis.

Bacterial Proteins↗

PubMed2005

Separation of thiamin and its phosphate esters by capillary zone electrophoresis and its application to the analysis of water-soluble vitamins.

A capillary zone electrophoresis method for the separation and determination of thiamin and its phosphate esters (free thiamin, thiamin monophosphate, and thiamin pyrophosphate) was developed and optimized. The efficiency achieved with boric acid-sodium tetraborate decahydrate buffer (pH 8.24; 65-8 mM) at an applied potential of 30 kV gave the detection limit (S/N = 3) and the limit of quantitative measurement (S/N = 10) of thiamin and its phosphate esters ranging from 10(-4) to 6 x 10(-4) mM and from 6 x 10(-4) to 1.2 x 10(-3) mM, respectively. The effects of pH on separation and migration times of thiamin and its phosphate esters are described. The method was validated and applied to the quantitative determination of thiamin in commercial tablets containing both a massive and a normal dose of thiamin.

Electrophoresis, Capillary↗