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PubMed1985

The inhibitory effect of choline and other quaternary ammonium compounds on thiamine transport in isolated rat hepatocytes.

Quaternary ammonium compounds, such as choline and acetylcholine significantly inhibited thiamine uptake in isolated rat hepatocytes. Kinetic analysis using Lineweaver-Burk and Dixon plots of inhibition experiments revealed that choline and acetylcholine were purely competitive inhibitors for thiamine uptake with Ki values of 0.61 mM and 0.31 mM, respectively. Among quaternary ammonium compounds, hemicholinium-3 and curare were the strongest inhibitors, and kinetic studies showed that these compounds were also purely competitive inhibitors with Ki values of 12.5 microM and 4.3 microM, respectively. These results indicate that choline, acetylcholine and their structural analogs share a common binding site with thiamine in isolated rat hepatocytes. On the other hand, choline uptake by isolated rat hepatocytes occurred by a saturable mechanism with a Kt of 162 +/- 3.85 microM and Vmax of 80.1 +/- 1.30 pmol/10(5) cells per min as well as by a nonsaturable mechanism. Thiamine, pyrithiamine, oxythiamine, chloroethylthiamine and dimethialium inhibited choline uptake, while thiamine phosphates such as thiamine monophosphate and thiamine pyrophosphate insignificantly inhibited uptake. Although a Lineweaver-Burk plot of choline uptake in the presence of thiamine showed that thiamine also competitively inhibited choline uptake, a Dixon plot of the inhibition experiment was hyperbolic and indicated that the inhibition of choline uptake by thiamine was 'pseudo-competitive'. On the basis of these results, it is suggested that in isolated rat hepatocytes thiamine and choline do not share common transport sites.

Animals↗

PubMed2002

Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria.

Thiamin and riboflavin are precursors of essential coenzymes-thiamin pyrophosphate (TPP) and flavin mononucleotide (FMN)/flavin adenine dinucleotide (FAD), respectively. In Bacillus spp, genes responsible for thiamin and riboflavin biosynthesis are organized in tightly controllable operons. Here, we demonstrate that the feedback regulation of riboflavin and thiamin genes relies on a novel transcription attenuation mechanism. A unique feature of this mechanism is the formation of specific complexes between a conserved leader region of the cognate RNA and FMN or TPP. In each case, the complex allows the termination hairpin to form and interrupt transcription prematurely. Thus, sensing small molecules by nascent RNA controls transcription elongation of riboflavin and thiamin operons and possibly other bacterial operons as well.

Bacillus subtilis↗

PubMed1990

Effects of acute and chronic ethanol administration on thiamine metabolizing enzymes in some brain areas and in other organs of the rat.

The effect of ethanol (4.7 g/kg body wt intragastrically as a single dose or once daily for 35 days) on the levels of the thiamine metabolizing enzymes (thiamine pyrophosphokinase, TPKase; thiamine pyrophosphatase, TPPase; and monophosphatase, TMPase) was studied in different organs (liver, kidney, small intestine, heart and skeletal muscle) and nervous regions (cerebral cortex, cerebellum, medulla oblongata, pons, corpus callosum, hypothalamus and sciatic nerve) of the rat. In order to evaluate the non-specific effects of the stress of gastric gavage and of the additional caloric intake, appropriate control groups of animals were treated intragastrically with water or with a saccharose solution isoenergetic with ethanol respectively. All animals were reared on a nutritionally adequate diet supplying amounts of thiamine higher than the recommended daily requirement. Enzymatic activities were determined quantitatively by biochemical methods. Tissue TPKase levels were generally reduced by both acute and chronic ethanol administration. TPPase levels were generally reduced after acute and increased after chronic ethanol treatment. Changes in brain TMPase levels were similar to those observed for TPPase. In visceral organs and skeletal muscle TMPase activity was increased by chronic ethanol treatment as compared to acute ethanol administration. In conclusion, ethanol exerts a marked influence on the tissue levels of the thiamine metabolizing enzymes: the activity of the enzymes dephosphorylating thiamine phosphates is increased whereas the activity of the thiamine pyrophosphate synthesizing enzyme is reduced. These changes may contribute to an important extent to the disturbances in thiamine cellular uptake and metabolism observed in alcoholism.

Alcoholic Intoxication↗

PubMed1981

Effects of chronic alcohol feeding on thiamin status: biochemical and neurological correlates.

The effects of chronic alcohol feeding on thiamin status are controversial; both adverse and beneficial effects have been reported. In order to study these effects, rats and baboons were pair-fed liquid diets containing thiamin in excess of dietary requirements and either ethanol (rats 36%, baboons 50% of total calories) or the identical diet with ethanol substituted isocalorically by carbohydrate. In the rat, chronic alcohol feeding for up to 6 months had no effects on tissue thiamin measured by transketolase assay, thiamin pyrophosphate effect, or bioassay with Ochromonas danica. Shuttle box avoidance learning in rats was impaired in animals rendered thiamin deficient but not in animals fed control or alcohol-containing liquid diets. In baboons, chronic alcohol feeding for up to 3 yr had no effects on blood levels of thiamin or on urinary excretion of thiamin. Thus, chronic alcohol feeding along with nutritionally supplemented diets does not appear to significantly affect thiamin status.

Animals↗

PubMed1984

Lactate and pyruvate production in isolated thiamine-deficient rat diaphragm strips.

Rats were maintained on a thiamine-deficient diet to deplete skeletal muscle of thiamine pyrophosphate, and thus decrease the oxidative metabolism of pyruvate. The blood lactate concentration was significantly elevated in thiamine-deficient (TD) animals when compared with pair-fed (TP) controls. Analysis of diaphragm strips from these animals revealed that tissue lactate and pyruvate concentrations were not affected by any of the treatments employed. The rate of lactate efflux from TD tissues was, however, twice that from TP and 4.5 times that from weight-control (WC) tissues. The H+ efflux rate was also much greater in the TD muscle preparation than either of the control groups. Following 3 min of stimulation (150-Hz, 200-ms pulse train every 0.5 s), the degree of fatigue of tissues from each of these three treatment groups was not different. The observation in this study that glycolysis becomes the predominant metabolic pathway in thiamine deficiency without increasing the intracellular level of products, indicates that this treatment also has other effects which increase the effective lactate permeability of the fibre membranes.

Animals↗

PubMed2002

Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics.

OBJECTIVE: To analyze the association of thiamin, selenium, and copper serum levels with cardiac function in patients with idiopathic dilated cardiomyopathy using diuretics, and also to compare them with levels in control patients with no evidence of disease. METHODS: The study comprised 30 patients with heart disease and 30 healthy control individuals. Thiamin was analyzed by measuring the activity of erythrocytic transketolase and the effect of thiamin pyrophosphate. Selenium and copper serum levels were measured by hydride generation and flame atomic absorption spectrophotometry, respectively. RESULTS: Thiamin deficiency was observed in 10% of the control individuals and in 33% of the patients with heart disease (p=0.02). The mean selenium and copper serum levels in control individuals and patients with heart disease were, respectively, 73.2+/-9.9 microg/L (56.5 to 94.5 microg/L) and 72.3+/-14.3 microg/L (35.5 to 94 microg/L) (p=0.77); 1.1+/-0.4 mg/L (0.6 to 1.8 mg/L) and 1.2+/- 0.4 mg/L (0.6 to 2.2 mg/L) (p=0.27). No association between the levels of these nutrients and cardiac function was observed. CONCLUSION: Thiamin deficiency was significantly more frequent in patients with heart disease. No significant difference was observed between the mean selenium and copper serum levels in control individuals and in patients with heart disease. The results suggest possible benefits with thiamin replacement in patients taking diuretics.

Adult↗

PubMed1994

Thiamine status of elderly patients with cardiac failure including the effects of supplementation.

This study compared the thiamine status of 35 elderly hospital inpatients with cardiac failure (CF) with that of 35 elderly inpatients with other diagnoses (Non-CF). The CF group was then randomly allocated to CF1 group (thiamine treatment, 200 mg per day for 7 days), and CF2 group (non supplemented). The effect of the thiamine treatment on the cardiac failure course was examined. Although there was no significant difference in thiamine status between CF and Non-CF groups, 11.5% of the first group against only 6.0% of the second was deficient with the thiamine pyrophosphate stimulation effect (TPPE) test. The same trend was observed, if NYHA functional assessment was taken into account, thiamine deficiency was more frequent in class 4 than in class 3. No significant difference for thiamin status was observed in patients receiving furosemide treatment and those without furosemide treatment. Although vitamin treatment permitted a significant improvement in thiamine status, the course of the cardiopathy was not significantly different in CF1 (supplemented) and CF2 (non supplemented) groups. Whether systematic thiamine supplementation is indicated in CF patients requires further investigation.

Aged↗

PubMed1981

Effects of level of dietary glutamic acid and thiamin on food intake, weight gain, plasma amino acids, and thiamin status of growing kittens.

Specific pathogen-free kittens were individually fed purified amino acid diets containing 4.4 mg of thiamin and 3.0, 4.5, 6.0, 9.0 or 12.0% glutamic acid (Glu) in a balanced 5 x 5 latin square design. Kittens fed either the 9.0% followed by the 12.0% glutamate diets or vice versa developed severe clinical signs of thiamin deficiency and two kittens died. Other affected kittens given 5 mg additional thiamin per day for 3 days promptly recovered. In a subsequent experiment, the effect of a diet containing 12.0% glutamic acid with either 4.4 or 25.0 mg thiamin per kilogram diet was compared with a diet containing 3.0% glutamic acid with either 0.0 or 4.4 mg thiamin per kilogram. Kittens fed the diet containing the high level of glutamic acid with 4.4 mg thiamin exhibited depressed food intake and body weight gain and an elevated level of plasma glutamic acid compared to diets containing 3.0% glutamic acid. Red blood cells from this group of kittens also showed a transitory incomplete saturation of transketolase with thiamin pyrophosphate. Kittens fed the high glutamate diets vomited occasionally during the 1st month of the dietary regimen. Although increased thiamin (25 mg/kg diet) decreased the severity of the adverse effects of the high glutamate diet, maximal growth was not obtained in kittens fed the high glutamate, high thiamin diet.

Amino Acids↗

PubMed1981

Biochemistry of natural and amprolium-induced polioencephalomalacia in sheep.

Polioencephalomalacia (PEM) induced in sheep was compared with the disease found in naturally occurring cases. Blood biochemical indicators measured were pyruvate, lactate, glucose, erythrocyte transketolase (TK) and stimulation of TK by addition of thiamine pyrophosphate (TPP effect). Faeces and rumen contents were assayed for thiaminase activity. The effect of treating affected sheep with thiamine was also noted. It was found that amprolium treatment could induce thrombocytopenia, but once the sheep became accustomed to amprolium in the diet they seemed to be resistant to this effect. In sheep receiving amprolium significant weight losses preceded the onset of clinical signs. Further weight loss continued throughout the recovery period despite removal of amprolium from the diet and treatment with thiamine. Blood glucose was variable, and was elevated only when marked clinical signs were present. Pyruvate and lactate levels showed marked variation throughout the trial. TK values were depressed and TPP effects increased well before the onset of clinical signs, although some naturally occurring cases had normal levels. Faecal thiaminase activity was negligible in all the sheep on the amprolium trial but most field cases had a high level. High faecal thiaminase was observed in about 5% of clinically normal animals from affected flocks. Depression of erythrocyte TK activity coupled with the presence of faecal thiaminase appeared to be the most reliable diagnostic biochemical parameters for PEM. Treatment of PEM affected sheep with thiamine rapidly brought the biochemical status of the animals to normal. However where advanced brain lesions were present the damage was permanent and such sheep treated with thiamine remained partially decorticate.

Amprolium↗

PubMed2002

Effects of furazolidone, PCB77, PCB126, Aroclor 1248, paraquat and p,p'-DDE on transketolase activity in embryonal chicken brain.

The effect of in ovo exposure to PCBs, DDE and paraquat on transketolase activity was measured in 19-day-old chicken embryos. Furazolidone was used as a positive control for decreased activity of the enzyme. The potency of contaminants to interact with transketolase was also tested in an in vitro system, using control brain 7000xg supernatants containing the enzyme. No effects were found on transketolase activity after in ovo or in vitro exposure to PCB126, Aroclor, DDE or paraquat. PCB77 decreased transketolase activity in vitro, but only at concentrations that, extrapolated to in ovo exposure, would be lethal to the embryo. Furazolidone decreased transketolase activity both in ovo and in vitro. For this contaminant, thiamine residues were analysed in the yolk sacs, but no differences were found between exposed and non-exposed eggs. Transketolase is dependent on thiamine pyrophosphate as a cofactor, and therefore, the decreased enzyme activity could be the result of an interaction between furazolidone and thiamine metabolism. Since thiamine residues were not affected by furazolidone and transketolase inhibition in vitro was similar to the inhibition after in ovo exposure, it was concluded that furazolidone interacted with transketolase on the enzymatic level rather than by a depletion of thiamine.

Animals↗

PubMed1986

Characterization of a retinylmonophosphatase in the plasma membrane of mouse brain.

Retinylmonophosphatase (RMPase) activity in mouse brain paralleled the subcellular distribution of the plasma-membrane marker Na+ + K+-dependent ATPase. The enzyme had a pH optimum between 5.5 and 7.0. The enzyme demonstrated linear kinetics with respect to time and both protein and substrate concentrations. RMPase was saturated by low retinyl monophosphate (RMP) concentrations and exhibited an apparent Km of 4.6 microM. The enzyme did not require MgCl2 for activity, and in fact assays were routinely run in the presence of 10 mM-Na2EDTA. In general, detergents inhibited the enzyme, with 0.05% Triton X-100 causing a 30% loss of activity. Phosphatidic acid was also inhibitory, but phosphatidylcholine and sphingomyelin stimulated phosphatase activity. RMPase was inhibited 35% by 5 mM concentrations of fluoride, phosphate or pyrophosphate. A series of other phosphorylated compounds, including glucose 6-phosphate, alpha-glycerophosphate, ATP, AMP, p-nitrophenyl phosphate and thiamin pyrophosphate, showed little or no inhibition. RMPase activity differed in several characteristics from that previously reported for dolichylmonophosphatase. It is concluded that RMP could play a distinct role in the plasma membrane.

Animals↗

PubMedDate not supplied

Experimentally induced beriberi polyneuropathy in chickens.

Chickens fed with the same composition of diet as our low income beriberi polyneuropathic patients, developed clinical symptoms of thiamine deficiency in 22.3 +/- 6.3 days. There appeared to be a body store of thiamine which is utilized during a period of deficient intake. Haemoglobin content and serum albumin did not change appreciably during thiamine deficiency. The blood thiamine content was low and the thiamine pyrophosphate (TPP) effect increased to more than 25 percent during the development of the beriberi polyneuropathy, which resumed after one week on thiamine tetrahydrofurfuryl disulfide (TTFD) treatment. However, the clinical features gradually improved after about one month. Neurophysiological findings including somatosensory evoked potentials (SSEPs) and neuromorphological studies of the peroneal and sciatic nerves were compatible with a major degree of axonal degeneration and secondary minimal segmental demyelination. We may conclude that the experimentally induced beriberi polyneuropathy in chickens seems a good model for studying these forms of neuropathy in view of diagnosis and treatment.

Animals↗

PubMed1989

Thiamine triphosphatase in the membranes of the main electric organ of Electrophorus electricus: substrate-enzyme interactions.

The main electric organ of Electrophorus electricus is particularly rich in thiamine triphosphate (TTP). Membrane fractions prepared from this tissue contain a thiamine triphosphatase that is strongly activated by anions and irreversibly inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an anion transport inhibitor. Kinetic parameters of the enzyme are markedly affected by the conditions of enzyme preparation: In crude membranes, the apparent Km is 1.8 mM and the pH optimum is 6.8, but trypsin treatment of these membranes or their purification on a sucrose gradient decreases both the apparent Km (to 0.2 mM) and the pH optimum (to 5.0). Anions such as NO3- (250 mM) have the opposite effect, i.e., even in purified membranes, the pH optimum is now 7.8 and the Km is 1.1 mM; at pH 7.8, NO3- increases the Vmax 24-fold. TTP protects against inhibition by DIDS, and the KD for TTP could be estimated to be 0.25 mM, a value close to the apparent Km measured in the same purified membrane preparation. Thiamine pyrophosphate (0.1 mM) did not protect against DIDS inhibition. At lower (10(-5)-10(-6) M) substrate concentrations, Lineweaver-Burk plots of thiamine triphosphatase activity markedly deviate from linearity, with the curve being concave downward. This suggests either anticooperative binding or the existence of binding sites with different affinities for TTP. The latter possibility is supported by binding data obtained using [gamma-32P]TTP. Our data suggest the existence of a high-affinity binding site (KD of approximately 0.5 microM) for the Mg-TTP complex.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2006

Thiamine deficiency and parasitic infection in rural Thai children.

A study was carried out to determine whether thiamine deficiency in northeast Thailand is linked with parasitic infection. We assessed the thiamine status and tested for parasitic infections in 231 children between 6 and 12 years of age in Nam Phong District of Khon Kaen Province, Thailand. Thiamine deficiency [thiamine pyrophosphate effect (TPPE) > 20%] and parasitic infections (mostly Strongyloides stercoralis) were identified in 16 and 45% of the children, respectively. No association between thiamine deficiency and parasitic infection was found. The general health of the children, according to Thai standard anthropometric curves, was within the normal range. The suboptimal thiamine status and the high prevalence of parasitic infection require attention.

Child↗

PubMed2001

The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study.

Thiamine deficiency frequently occurs in patients with advanced cancer and therefore thiamine supplementation is used as nutritional support. Thiamine (vitamin B1) is metabolized to thiamine pyrophosphate, the cofactor of transketolase, which is involved in ribose synthesis, necessary for cell replication. Thus, it is important to determine whether the benefits of thiamine supplementation outweigh the risks of tumor proliferation. Using oxythiamine (an irreversible inhibitor of transketolase) and metabolic control analysis (MCA) methods, we measured an in vivo tumour growth control coefficient of 0.9 for the thiamine-transketolase complex in mice with Ehrlich's ascites tumour. Thus, transketolase enzyme and thiamine clearly determine cell proliferation in the Ehrlich's ascites tumour model. This high control coefficient allows us to predict that in advanced tumours, which are commonly thiamine deficient, supplementation of thiamine could significantly increase tumour growth through transketolase activation. The effect of thiamine supplementation on tumour proliferation was demonstrated by in vivo experiments in mice with the ascites tumour. Thiamine supplementation in doses between 12.5 and 250 times the recommended dietary allowance (RDA) for mice were administered starting on day four of tumour inoculation. We observed a high stimulatory effect on tumour growth of 164% compared to controls at a thiamine dose of 25 times the RDA. This growth stimulatory effect was predicted on the basis of correction of the pre-existing level of thiamine deficiency (42%), as assayed by the cofactor/enzyme ratio. Interestingly, at very high overdoses of thiamine, approximately 2500 times the RDA, thiamine supplementation had the opposite effect and caused 10% inhibition of tumour growth. This effect was heightened, resulting in a 36% decrease, when thiamine supplementation was administered from the 7th day prior to tumour inoculation. Our results show that thiamine supplementation sufficient to correct existing thiamine deficiency stimulates tumour proliferation as predicted by MCA. The tumour inhibitory effect at high doses of thiamine is unexplained and merits further study.

Animals↗

PubMed1987

Development of the alt Mutant of Pisum sativum L.

The alt (albina-terminalis) mutant of Pisum sativum L. germinates normally, produces several nodes, and then above a sharp transition produces 2 to 3 bleached nodes, ceases growth, and eventually dies. Green nodes have normal chlorophyll content, absorption spectra, photosynthetic rates, and ultrastructure. In bleaching tissues, the chloroplasts degenerate rapidly, followed by extensive disruption and loss of the remaining cytoplasm and organelles. Application of tissue extracts of normal genotypes of pea, corn, and bean stimulates apical development of alt. The resulting tissues have essentially normal structure and function. Application of thiamine, thiamine monophosphate, and thiamine pyrophosphate also stimulate normal apical development at concentrations of 1 micromolar and above. Partial characterization of the stimulus from pea seed extracts is consistent with thiamine as the active factor.

Journal Article↗

PubMed2005

Thiamine deficiency in dogs due to the feeding of sulphite preserved meat.

A 6-year-old dog, a 4-year-old dog and three 7-week-old puppies were diagnosed with thiamine deficiency caused by feeding sulphite treated meat. The 6-year-old dog presented with a history of inappetence, weight loss and vomiting that rapidly progressed to signs of multifocal intracranial disease including mental dullness, paresis, seizures, spontaneous nystagmus and strabismus. Thiamine pyrophosphate effect was elevated at 58% and magnetic resonance imaging revealed bilaterally symmetrical hyperintensity of the caudate nucleus and rostral colliculi. The dog recovered with thiamine supplementation. The 4-year-old dog and three 7-week-old puppies also presented with rapidly progressive multifocal central nervous system signs including ataxia, paresis, increased muscle tone, seizures, nystagmus and exophthalmos. The 4-year-old dog made a rapid recovery with thiamine supplementation. Euthanasia and necropsy of a puppy revealed malacia of multiple brainstem nuclei and oedema of the cerebral cortex. These findings were consistent with thiamine deficiency.

Animal Feed↗

PubMed1993

Cloning of human transketolase cDNAs and comparison of the nucleotide sequence of the coding region in Wernicke-Korsakoff and non-Wernicke-Korsakoff individuals.

Variants of the enzyme transketolase which possess reduced affinity for its cofactor thiamine pyrophosphate (high apparent Km) have been described in chronic alcoholic patients with Wernicke-Korsakoff syndrome. Since the syndrome has been shown to be directly related to thiamine deficiency, it has been hypothesized that such transketolase variants may represent a genetic predisposition to the development of this syndrome. To test this hypothesis, human transketolase cDNA clones were isolated, and their nucleotide and predicted amino acid sequence were determined. Transketolase was found to be a single copy gene which produces a single mRNA of approximately 2100 nucleotides. Additionally, the nucleotide sequence of the transketolase coding region in fibroblasts derived from two Wernicke-Korsakoff (WK) patients was compared to that of two nonalcoholic controls. Although nucleotide and predicted amino acid differences were detected between fibroblast cultures and the original cDNAs and among the cultures themselves, no specific nucleotide variations, which would encode a variant amino acid sequence, were associated exclusively with the coding region from WK patients. Thus, allelic variants of the transketolase gene cannot account for the biochemically distinct forms of the enzyme found in these patients nor be considered as a mechanism for genetic predisposition to the development of Wernicke-Korsakoff syndrome. Instead, the underlying mechanism must be extragenic and may be a result of differences in post-translational processing/modification of the transketolase polypeptide.

Alcohol Amnestic Disorder↗