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PubMed1993

Pathophysiologic mechanisms responsible for the reversible (thiamine-responsive) and irreversible (thiamine non-responsive) neurological symptoms of Wernicke's encephalopathy.

Chronic alcoholism results in thiamine deficiency as a result of poor nutrition and impaired gastrointestinal absorption of the vitamin. Pyrithiamine-induced thiamine deficiency in the rat reproduces a neurological syndrome and ultimately neuropathological damage of a nature and distribution that is similar to that encountered in Wernicke's encephalopathy in humans. Pyrithiamine-induced thiamine deficiency results in selective reversible decreases in activity of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase and concomitant reversible changes in brain amino acids. It is proposed that these changes constitute "the biochemical lesion" in thiamine deficiency encephalopathy. If sufficiently severe and prolonged, decreased activities of alpha-ketoglutarate dehydrogenase may result in compromised brain energy metabolism and in lactate accumulation in brain, both of which could be responsible for neuronal cell death in this condition. In addition, it has been suggested that cell death results from NMDA-receptor mediated excitotoxic damage. Similar pathophysiologic mechanisms could be responsible for brain cell death in Wernicke's encephalopathy in humans.

Journal Article↗
PubMed1999

Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect.

BACKGROUND AND AIMS: The aim of the study was to determine the thiamin status in HIV-positive patients. METHODS: Measurement of erythrocyte transketolase activity (ETK) and thiaminpyrophosphate (TPP) effect in 55 consecutive HIV-positive patients of a specialized outpatient clinic were grouped into five groups according to their CD4 counts. Comparison of results of HIV-positive patients with age-matched control group of 22 healthy subjects. RESULTS: Of the patients, 27% had a pathologically-increased TPP effect, 18% of the patients had pathologically-low ETK. The percentage of pathological values of TPP effect in the patients was significantly higher compared with the control group. There was no statistically significant correlation between pathological thiamin status and stage of the disease, zidovudine therapy or nutritional status of the patients. CONCLUSIONS: Thiamin deficiency in HIV-positive patients was found in a higher percentage than previously reported. Thiamine deficiency is not only present in advanced stages of HIV-infection, but also in clinically asymptomatic patients.

Adult↗
PubMed1998

Thiamine pyrophosphate-dependent and thiamine metabolizing enzymes in the deafferented cerebellum and in the intact cerebral cortex of rat.

The effects of chemical (CD) and surgical (SD) deafferentation of the cerebellum on thiamine pyrophosphate (ThPP)- dependent enzymes (transketolase, TK; pyruvate-, PDH, and alpha-ketoglutarate, alphaKGDH, dehydrogenases) and thiamine (Th) metabolizing enzymes (thiamine pyrophosphokinase, ThPK; thiamine mono-, ThMPase, and pyrophosphatases, ThPPase) were evaluated in vitro in rats in steady state conditions. The enzymes were also determined in the intact cerebral cortex of the same animals. CD was carried out by i.p. injection of 3-acetylpyridine, followed by harmaline and niacinamide. SD was carried out by complete dissection of the peduncles of the left cerebellar hemisphere. Chemical and surgical cerebellar deafferentations significantly lowered the contents of both Th-metabolizing and ThPP-dependent enzymes in the cerebellum without modifying those of the cerebral cortex. ThPK and TK, which are particularly concentrated in neurons, were the most affected enzymes. The decrease in ThPP-dependent enzymes shown here is associated with the slowing down of the Th phosphorylation-dephosphorylation cycle and with no modification in the ThPP content in the cerebellum, both of which were found in a previous study. Cerebellar deafferentation seems to only affect the apoenzyme moiety of the enzymes.

Afferent Pathways↗
PubMed1995

Schizosaccharomyces pombe thiamine pyrophosphokinase is encoded by gene tnr3 and is a regulator of thiamine metabolism, phosphate metabolism, mating, and growth.

The Schizosaccharomyces pombe gene tnr3 has been genetically defined as a negative regulator of genes involved in thiamine metabolism (Schweingruber, A. M., Frankhauser, H., Dlugonski, J., Steinmann-Loss, C., and Schweingruber, M. E. (1992) Genetics 130, 445-449). We have isolated and sequenced the gene and show that it codes for a putative protein of 569 amino acids which exhibits, in its carboxyl-terminal half, good homology to Saccharomyces cerevisiae thiamine pyrophosphokinase (TPK). tnr3 mutants have reduced levels of intracellular thiamine diphosphate, show impaired TPK activity, which is enhanced by introducing the tnr3 wild type gene on a plasmid, and can be complemented by the S. cerevisiae TPK-encoding gene TH180. These data strongly suggest that tnr3 encodes S. pombe TPK. We present evidence that TPK also acts as a negative regulator for gene pho1, which is derepressed when cells are starved for phosphate and show that in contrast to wild type cells, tnr3 mutants mate constitutively in response to thiamine, indicating that TPK is also involved in regulation of mating. Disruption of the tnr3 gene is lethal, and a tnr3 mutant expressing only residual TPK activity grows slowly and shows aberrant morphology.

Acid Phosphatase↗
PubMed1990

Effects of thiamine administration on hypothermia and hypothalamic histamine levels in dietary-induced thiamine deficient rats.

The rats maintained on a thiamine-deficient diet for 30 days showed hypothermia, and their histamine levels increased significantly in both the anterior and posterior hypothalamus. When these rats were administered, thiamine disulfide and/or provided with thiamine-added diet for a further 30 days, the rats recovered from hypothermia, and histamine levels were decreased to the normal level. Thus, it is probable that the increased histamine levels in the hypothalamus, especially those in its anterior region, are closely related to the hypothermia in thiamine-deficient rats.

Animals↗
PubMed2006

Thiamin nutrition and catalysis-induced instability of thiamin diphosphate.

Thiamin (vitamin B1) is required in animal diets because it is the precursor of the enzyme cofactor, thiamin diphosphate. Unlike other B vitamins, the dietary thiamin requirement is proportional to non-fat energy intake but there is no obvious biochemical reason for this relationship. In the present communication we show for two enzymes that the cofactor undergoes a slow destruction during catalysis, which may explain the interdependence of thiamin and energy intakes.

Acetolactate Synthase↗
PubMed1984

Nervous tissue thiamine metabolism in vivo. II. Thiamine and its phosphoesters dynamics in different brain regions and sciatic nerve of the rat.

Different steps of the metabolism of thiamine (T), thiamine mono- (TMP), pyro- (TPP) and triphosphate (TTP) in the cerebellum, brainstem, cerebral cortex and the sciatic nerve were evaluated in the rat in vivo. The radioactivity of T and its phosphoesters was determined at fixed time intervals (0.5-240 h) after an intraperitoneal injection of [14C]T (30 micrograms:1.25 muCi), under steady state conditions. The dynamics of thiamine compounds was evaluated using a compartmental mathematical model that allowed the fractional rate constants (FRC), turnover rates (TR) and turnover times to be calculated. The phosphorylation of T to TPP and the dephosphorylations of TPP to TMP and TMP to T could be estimated in all the structures investigated. Their turnover rates were found to be ordered in the sequence: cerebellum greater than brainstem greater than cerebral cortex greater than sciatic nerve. The transphosphorylation of TPP to TTP was so small that it could not be determined in a reliable way. Regional differences were found both the rate and in the composition of T and TMP mixture released from nervous structures. The shortest turnover time of TPP was found in the cerebellum, while the sciatic nerve exhibited the fastest renewal of T and TMP. In all the structures investigated TPP had a rather short turnover time, suggesting that its function might be associated to a rapid conversion into chemically different forms. The possible relationships between the rates of turnover of T compounds are the sensitivity of the nervous structures to T deficiency are discussed.

Animals↗
PubMed1986

Thiamine-deficient encephalopathy in rats: effects of deficiencies of thiamine and magnesium.

Thiamine- and vitamin B-deficient encephalopathy was produced in adult Wistar rats and the effect of magnesium deprivation and/or the administration of guanidine, a magnesium antagonist, was studied. These encephalopathic rats had symmetrical lesions, edema, exudation of fibrin, spongy changes, petechial hemorrhages, neuronal degeneration and gliosis in the pontine tegmentum, mainly the lateral and medial vestibular nuclear areas. Mild pathological changes were seen in the purely thiamine- or vitamin B-deficient rats, whereas severe pathological changes occurred in thiamine- or vitamin B-deficient rats combined with magnesium deprivation and/or guanidine administration. However, magnesium-deficient diets or guanidine administration did not produce pathologic changes in rats. These findings suggest that thiamine deficiency is an essential factor in the development of these pathological changes in the brainstem, and that magnesium and guanidine, an antagonist of magnesium, play important roles in the development of these disorders.

Animals↗
PubMed1999

Ligand-protein interaction in plant seed thiamine-binding proteins. Binding of various thiamine analogues to the sepharose-immobilized buckwheat-seed protein.

Soluble thiamine-binding proteins occur in microorganisms, some animal tissues, and plant seeds. Their representative, the buckwheat-seed protein, was chosen as a model for chemical studies on the mechanism of ligand-protein interaction in these systems. In this work, in order to refine a concept of the chemical topography of the thiamine-binding center, the buckwheat seed protein was immobilized in Sepharose gel and probed with a new set of thiamine-related compounds. In terms of the standard change of Gibbs free energy on the complex formation, the following energetic contributions were specifically assigned to major structural features of the thiamine molecule: (i) 35-45% to the specific electronic structure of planar, unsaturated thiazolium ring with positive charge asymmetrically delocalized, one half of that contribution being attributable to the S(1) atom, (ii) 11-18% to nitrogen atoms and their electronic coupling within the pyrimidine ring, (iii) 15% to the 4'-amino group, and (iv) less than 10% to the hydroxyethyl chain.

Binding Sites↗
PubMed1999

Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome.

Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus. Treatment with pharmacologic doses of thiamine ameliorates the megaloblastic anaemia and diabetes mellitus. A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cultured skin fibroblasts from TRMA patients. The gene causing TRMA was assigned to 1q23.2-q23.3 by linkage analysis. Here we report the cloning of a new gene, SLC19A2, identified from high-through-put genomic sequences due to homology with SLC19A1, encoding reduced folate carrier 1 (refs 8-10). We cloned the entire coding region by screening a human fetal brain cDNA library. SLC19A2 encodes a protein (of 497 aa) predicted to have 12 transmembrane domains. We identified 2 frameshift mutations in exon 2. a 1-bp insertion and a 2-bp deletion, among four Iranian families with TRMA. The sequence homology and predicted structure of SLC19A2, as well as its role in TRMA, suggest that its gene product is a thiamine carrier, the first to be identified in complex eukaryotes.

Amino Acid Sequence↗
PubMed1977

The passage of thiamine across the rat placenta and its uptake by the fetal organs. II. The uptake of thiamine by fetal organs.

Having injected 3H-thiamine into the maternal bloodstream of rats in their 15th day of pregnancy, the uptake by the fetal organs (liver and cardiac muscle) of the 3H-thiamine which had been transported across the placenta was studied by electron microscope autoradiography and by measuring the radio-activity of the tissues, using the same methods reported in the first paper of this series. In the fetal liver both developed silver grains and radioactivity were found in greates amounts in specimens collected 5 hrs after injection. Developed silver grains were abundant in the mitochrondria, Golgi apparatus, rough-surfaced endoplasmic reticulum, glycogen area, and nucleus, indicating that these cell organelles take up thiamine and utilize it for the cell metabolism. In the fetal cardiac muscle, the developed silver grains and radioactivity were found in greatest amounts 2 hrs after injection. The silver grains were abundant in the glycogen area, Golgi apparatus, and myofibrils, but they were especially abundant in the mitochondria. This indicates that thiamine is taken up by these organelles and employed in the cell metabolism.

Animals↗
PubMed1985

Assessment of the thiamine nutritional status. An evaluation of erythrocyte transketolase activity, the stimulated erythrocyte transketolase activity, and the thiamine pyrophosphate effect.

The most widely accepted approach to estimation of thiamine nutrition has been the measurement of the erythrocyte transketolase activity (ETKA), the ETKA stimulated in vitro with thiamine pyrophosphate (TPP) (which is suggested to be designated ETKAS) and the percentage increase of ETKA after stimulation with TPP in vitro, called the thiamine pyrophosphate effect (TPPE). In spite of 30 years of experience in the determination of these variables doubtfulness still exists of how to assess them. On the basis of a study of a group of alcoholics and a group of non-alcoholics a system of evaluation of ETKA, ETKAS and TPPE is proposed.

Adult↗
PubMed1991

Application of high-performance liquid chromatography to the study of thiamine metabolism and in particular thiamine triphosphatase.

Thiamine triphosphate can be found in most tissues at very low levels, but its role is unknown. Organs and muscles that generate electrical impulses are particularly rich in this compound. This paper describes a thiamine triphosphatase from the electrical organ of Electrophorus electricus. The activity of this enzyme, as measured by a high-performance liquid chromatographic method, is closely anion-regulated. Furthermore, thiamine triphosphate increases chloride uptake in membrane vesicles prepared from rat brain. Our results suggest that this compound could play an important role in the regulation of chloride permeability.

Animals↗
PubMed1989

Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes.

Pyrithiamine-induced thiamine-deficiency encephalopathy in the rat shows many neuropathological and biochemical similarities to Wernicke's encephalopathy in humans. Treatment of rats with pyrithiamine resulted in moderate reductions of glutamate in thalamus and pons and in generalized severe reductions of aspartate in pons (by 89%, p less than 0.01), thalamus (by 83%, p less than 0.01), cerebellum (by 53%, p less than 0.01), and cerebral cortex (by 33%, p less than 0.05). Alanine concentrations were concomitantly increased. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were decreased in parallel with the aspartate decreases; pyruvate dehydrogenase complex activities were unchanged in all brain regions. Following thiamine administration to symptomatic pyrithiamine-treated rats, neurological symptoms were reversed and concentrations of glutamate, aspartate, and alanine, as well as alpha KGDH activities, were restored to normal in cerebral cortex and pons. Aspartate levels and alpha KGDH activities remained below normal values, however, in thalamus. Thus, pyrithiamine treatment leads to reductions of cerebral alpha KGDH and (1) decreased glucose (pyruvate) oxidation resulting in accumulation of alanine and (2) decreased brain content of glutamate and aspartate. Such changes may be of key significance in the pathophysiology of the reversible and irreversible signs of Wernicke's encephalopathy in humans.

Alanine↗
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↗
PubMedDate not supplied

Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome (OMIM No. 249270) comprises a distinctive triad of clinical features: megaloblastic anemia with ringed sideroblasts, diabetes mellitus, and progressive sensorineural deafness. The TRMA gene has been mapped and cloned. Designated "SLC19A2" as a member of the solute carrier gene superfamily, this gene is mutated in all TRMA kindreds studied to date. The product of the SLC19A2 gene is a membrane protein which transports thiamine (vitamin B1) with sub-micromolar affinity. Cells from TRMA patients are uniquely sensitive to thiamine depletion to the nanomolar range, while pharmacologic doses of vitamin B1 ameliorate the anemia and diabetes. Here we review the current status of studies aimed at understanding the pathophysiology of this unique transport defect.

Anemia, Megaloblastic↗
PubMed1975

[Thiamine in irradiated foodstuffs. II. Combined effects of irradiation, storage and cooking on the thiamine content (author's transl)].

The effects of 10 MeV electron radiation, of storage for several months and of heating on the thiamine content of wheat flour, crushed oats, ground pork, and dried whole egg were studied. A synergistic effect of these treatments on thiamine losses was observed. In irradiated samples thiamine content was more affected by storage and heating than in unirradiated ones.

Edible Grain↗