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PubMed2006

Characteristics of thiamine uptake by the BeWo human trophoblast cell line.

Little is known concerning the mechanisms responsible for the transplacental transfer of thiamine. So, the aim of this work was to characterize the placental uptake of thiamine from the maternal circulation, by determining the characteristics of 3H-thiamine uptake by a human trophoblast cell line (BeWo). Uptake of (3)H-thiamine (50-100 nM) by BeWo cells was: 1) temperature-dependent and energy-independent; 2) pH-dependent (uptake increased as the extracellular medium pH decreased); 3) Na(+)-dependent and Cl(-)-independent; 4) not inhibited by the thiamine structural analogs amprolium, oxythiamine and thiamine pyrophosphate; 5) inhibited by the unrelated organic cations guanidine, N-methylnicotinamide, tetraethylammonium, clonidine and cimetidine; 6) inhibited by the organic cation serotonin, and by two selective inhibitors of the serotonin plasmalemmal transporter (hSERT), fluoxetine and desipramine. We conclude that (3)H-thiamine uptake by BeWo cells seems to occur through a process distinct from thiamine transporter-1 (hThTr-1) and thiamine transporter-2 (hThTr-2). Rather, it seems to involve hSERT. Moreover, chronic (48 h) exposure of cells to caffeine (1 microM) stimulated and chronic exposure to xanthohumol and iso-xanthohumol (1 and 0.1 microM, respectively) inhibited (3)H-thiamine uptake, these effects being not mediated through modulation of the expression levels of either hThTr-1 or hSERT mRNA.

Biological Transport↗

PubMed1988

A Nuclear Mutation in Nicotiana sylvestris Causing a Thiamine-Reversible Defect in Synthesis of Chloroplast Pigments.

We report the recovery of a nuclear recessive mutation in Nicotiana sylvestris (Spegazzini and Comes) producing a conditional disruption in the pathway for synthesis of chlorophyll a and b and carotenoids which is fully reversible by exogenous thiamine (0.3 micromolar). In the absence of supplemental thiamine, chlorophyll levels declined by 50% after 5 days, and fell to undetectable levels by 11 days. Mitochondrial (KCN sensitive) respiration rates remained normal in albino leaves (80% loss of chlorophyll), suggesting that chlorosis results primarily from a deficiency of thiamine in the chloroplasts. After thiamine removal, mutant plants produced at least 10 albino leaves with a substantial capacity for growth (0-15 centimeters; 70-fold increase in area), demonstrating sustained operation of many cellular functions in spite of chloroplast disruption. Activities of the plastid isozymes of phosphoglucomutase and phosphoglucoisomerase in albino leaves indicated that the decline in pigment synthesis does not result from a general loss of metabolic activity in chloroplast. Plastid pyruvate dehydrogenase from mutant and wild-type plants displayed a similar affinity for thiamine pyrophosphate, showing that chlorosis does not result from an alteration in this enzyme. Growth of albino leaves and ultrastructural evidence for thylakoid membranes in the chloroplasts suggest that a certain level of fatty acid synthesis is maintained after the interruption of pigment synthesis. Since thiamine deprivation is expected to block production of acetyl-coenzyme A from pyruvate by pyruvate dehydrogenase, acetyl-coenzyme A supporting fatty acid synthesis in albino leaves may be derived solely from mitochondrial acetate.

Journal Article↗

PubMed2006

Effect of B vitamins-fortified foods on primary school children in Beijing.

The objective of this study is to investigate the effect of B vitamins-fortified foods on primary school children. A controlled trial was conducted in 101 normal primary school children aged 9-11 years. They were randomly assigned to supplemental control group (S-control, n=36), riboflavin supplementation group (+riboflavin 0.625 mg/day, n=32), and B vitamin compound supplementation group (+riboflavin 0.625 mg/day, +thiamin 0.512 mg/day, +nicotinic acid 0.365 mg/day, +folic acid 0.13 mg/day, n=33) based on school classes. Urinary riboflavin excretion and erythrocyte glutathione reductase activity coefficient (EGRAC) along with erythrocyte transketolase activity (ETKA) were used to evaluate B vitamin levels in the children. AYP index, an index reflecting the brain performance ability, was chosen to assess the children's study abilities. Health education was carried out to help children and their parents adopt scientific dietary concepts. The urinary riboflavin excretion was higher in two supplementation groups (435.24 +/- 153.3 microg/g creatinine, 374.6 +/- 144.6 microg/g creatinine) than in S-control group (235.1 +/- 86.2 microg/g creatinine). Average values of EGRAC were lower in two supplementation groups (0.90 +/- 0.11, 0.80 +/- 0.10) than in S-control group (1.08 +/- 0.25). At the same time, the percentage of thiamine pyrophosphate (TPP%) decreased from 63.69 +/- 28.04 to 42.16 +/- 16.31 in B vitamin compound supplementation group. Meanwhile, AYP index increased at the end of the supplementation in two supplementation groups. B vitamins supplementation can significantly increase B vitamin level in children. Biochemical activities of riboflavin and thiamin can improve with the intake of fortified foods. The effect of B vitamin compound supplementation is better than that of single riboflavin supplementation when the effect of riboflavin's biofunction is considered. In addition, micronutrient supplementation appears to assist children's study abilities.

Child↗

PubMed1990

Hypothesis and case reports: possible thiamin deficiency.

Three family members are reported with functional symptoms considered to be caused by intracellular deficiency of thiamin. Persistence of desaturation of erythrocyte transketolase in the face of megadose thiamin hydrochloride (THCl), accompanied by a balanced multivitamin and mineral formula, suggested a familial thiamin dependency state. Each of three individuals responded clinically to the administration of thiamin tetrahydrofurfuryl disulfide (TTFD), and erythrocyte transketolase (TKA) became fully saturated with thiamin pyrophosphate (TPP). Dysautonomic symptoms observed are compared with those seen in classical beriberi, the nutritional prototype for dysautonomia, and changes in blood pressure are described which support this premise. Although there is no proof from the laboratory, it is hypothesized that the biochemical lesion might be due either to malabsorption of thiamin or its inadequate phosphorylation.

Adult↗

PubMed2000

Thiamin status in furosemide-treated rats.

Rats were treated with furosemide at intraperitoneal doses of 10, 20, and 30 mg kg(-1)day(-1)for 21 days, and some indices of thiamin status (liver, blood and urine thiamin concentrations, erythrocyte transketolase (TK) activity, and thiamin pyrophosphate (TPP) effect, which refers to the increase in TK activity in a deficient haemolysate due to the addition of TPP before incubation) were measured. The results indicated that, at doses of 20 and 30 mg kg(-1)(but not 10 mg kg(-1)), furosemide produced significant effects on these indices suggestive of thiamin deficiency. In another experiment, the effect of thiamin treatment (20 and 100 microg kg(-1)) in rats concomitantly given furosemide (30 mg kg(-1)) was investigated. The high dose of the vitamin was sufficient to overcome the biochemical signs of thiamin deficiency induced by furosemide.

Animals↗

PubMed1999

Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% +/- 0.60% (mean +/- SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 microL/min. Fractional excretion of sodium (FE(Na)) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

Animals↗

PubMed1996

Thiamine administration during chronic alcohol intake in pregnant and lactating rats: effects on the offspring neurobehavioural development.

A number of mechanisms may be involved in the pathogenesis of thiamine deficiency in the alcoholic. Among these mechanisms are inadequate dietary intake of thiamine, impaired intestinal transport of the vitamin and decreased conversion of thiamine to the active coenzyme. The present study was undertaken to further investigate the mechanism by which alcohol can interfere with thiamine deficiency in the brain. Thus, the neurobehavioural development of rat pups (E) nursed by 12% ethanol/water-drinking mothers, or pups (E-T) nursed by mothers drinking 12% ethanol/water + thiamine hydrochloride mixture, was monitored from the 1st to 45th postnatal days. Appropriate pair-fed saccharose (S) and ad libitum controls (C) were assessed. Histological studies were performed at the age of 45 days on the hippocampal CA3 pyramidal neurons of the offspring from each treatment. Exposing rat pups to ethanol during pregnancy and lactation showed a significant impairment of neurobehavioural development, more cornered pyramidal cells in the hippocampal field CA3, reduced cell number and cell size. The results point out long-lasting effects of maternal alcohol exposure in the offspring. Both functional and structural studies showed that neurotoxic effects of developmental alcohol exposure were not reversed by thiamine administration. However, adverse effects of undernutrition following developmental alcohol exposure were suppressed by thiamine administration. From this work, we suggest that inadequate dietary intake of thiamine and impaired intestinal transport of the vitamin are not critical mechanisms leading to thiamine deficiency in chronic alcoholism. The most prevalent mechanism contributing to ethanol-induced thiamine deficiency in chronic alcoholics would be the alteration of thiamine metabolism, and particularly the reduction of the vitamin conversion to its metabolically active form TPP (thiamine pyrophosphate).

Animals↗

PubMed1975

Studies on the metabolism of beta-hydroxy- aspartic acid.

The content of beta-hydroxyaspartic acid was measured in the urine of man and several species of animals. The configuration of urinary beta-hydroxyaspartic acid was deduced to be L-erythro in form by chromatographic comparisons with authentic samples. An increased excretion of urinary beta-hydroxyaspartic acid was observed in cats when serine or thiamine was administered with glycine. Glycine-1-14C administered to rats was incorporated into the urinary beta-hydroxyaspartic acid. The formation of beta-hydroxyaspartic acid in pig-liver homogenate increased in the presence of glutamate and thiamine pyrophosphate. These results were discussed in relation to the author's working hypothesis on the biosynthesis of beta-hydroxyaspartic acid.

Animals↗

PubMed1986

Purification and characterization of, and preparation of an antibody to, transketolase from human red blood cells.

Transketolase (sedoheptulose-7-phosphate: D-glyceraldehyde-3-phosphate glycolaldehydetransferase, EC 2.2.1.1) was purified 16 000-fold from human red blood cells, using DEAE-Sephadex A-50, Sephadex G-150, FPLC on Mono P, and Sephadex G-100. The purified enzyme migrated as a single protein band on SDS-polyacrylamide gel electrophoresis. The FPLC step resolved transketolase into three peaks, designated I, II and III. From results of re-FPLC on Mono P, SDS-polyacrylamide gel electrophoresis, gel filtration, catalytic studies, amino acid analysis and immunological studies, it was concluded that I, II and III were originally the same protein, modified during storage and purification. Transketolase had a subunit (Mr 70 000) and appeared to be composed of two identical subunits. 1 mol of subunit contained 0.9 mol of thiamine pyrophosphate. The pH optimum of the reaction lay within the range 7.6-8.0, and the Km values were determined to be 1.5 X 10(-4) M for xylulose 5-phosphate and 4.0 X 10(-4) M for ribose 5-phosphate. Hg2+ and p-chloromercuribenzoate inhibited the enzyme reaction, and the inhibition of the latter disappeared upon the addition of cysteine. Thiamine and its phosphate esters did not, but cysteine (1 X 10(-2) M) and ethanol (10% and 1% v/v) did activate the enzyme reaction. Antibody prepared to II bound all forms of transketolase in the hemolysate, but inhibited the reaction only about 20%.

Amino Acids↗

PubMed2004

Role of vitamin-zinc interactions on in vitro zinc uptake by human erythrocytes.

In vitro zinc uptake by human erythrocytes was studied under a range of zinc concentrations representing three different plasma zinc levels i.e., zinc deficient [0.35-0.61 ppm], zinc normal [0.74-1.59 ppm], and zinc excess [1.65-2.3 ppm]. Further, interactions of physiological levels of riboflavin, flavin adenine dinucleotide (FAD), nicotinic acid, nicotinamide adenine dinucleotide (NAD), thiamine, thiamine pyrophosphate (TPP), folic acid, and ascorbic acid with zinc uptakes were studied in independent experiments. In control experiments, as compared to the normal zinc state, the rate of change of zinc uptake over change in zinc levels was 1.6 times in the excess state and 0.12 times in the deficient state, indicating three distinct patterns. Under the zinc-deficient state, thiamine significantly enhanced the zinc uptakes (p< 0.05), whereas ascorbic acid and riboflavin inhibited zinc uptakes (p< 0.05). The percent hemolysis of the cells was also significantly lower in the presence of thiamine (p< 0.05). Under normal and excess zinc states, the vitamin-zinc interactions were not significant. The results suggest that with erythrocytes as the vehicles, thiamine might be playing an enhancer role in uptake of zinc, whereas the action of ascorbic acid might be inhibitory for zinc uptakes under deficient zinc states.

Dose-Response Relationship, Drug↗

PubMed1989

Vitamin supplementation of patients receiving haemodialysis.

In order to assess the necessity of vitamin supplementation for patients who are receiving haemodialysis, measurements of vitamin status were made, and both dietary and supplementary intakes were assessed, in 26 patients who were undergoing haemodialysis. Blood samples were collected from these patients before they underwent haemodialysis, after an overnight fast, for the measurement of plasma retinol, alpha-tocopherol and ascorbate levels. Serum and erythrocyte folate levels were measured also. Thiamin status was assessed by the effect of added thiamin pyrophosphate on erythrocyte transketolase activity and pyridoxine status was assessed by the effect of added pyridoxal-5'-phosphate on erythrocyte aminotransferase activity. All patients had elevated plasma retinol levels; 48% of patients had elevated plasma alpha-tocopherol levels; the plasma ascorbate level was low in 50% of patients but was elevated in 25% of patients; and plasma and erythrocyte folate levels were elevated in 76% and 91% of patients, respectively. Thiamin status was normal in all but one patient and the pyridoxine level appeared to be low in two other patients. Many patients had low dietary intakes of vitamin C, folate and vitamin B6. We conclude that supplements of vitamins A and E are not required and, when dietary intakes of water-soluble vitamins are marginal, these should be supplemented at a dose as near as possible to the recommended dietary intake.

Ascorbic Acid↗

PubMed1987

Inorganic pyrophosphatase activity in cell-free extracts of Ureaplasma urealyticum.

Cell-free extracts of Ureaplasma urealyticum strains Pi and T960 (CX8) (serovars 6 and 8, respectively) metabolized inorganic pyrophosphate (PPi). The inorganic pyrophosphatase (PPase) activity was greatest with Mg2+ as cofactor, but Mn2+ acted as a poor substitute. The PPases of the two serovars differed electrophoretically. Although the highest PPase activity was obtained using PPi as substrate, the enzyme could also utilize to a lesser degree both tripolyphosphate and trimetaphosphate. No activity was observed against beta-glycerophosphate, naphthyl phosphates, glucose 6-phosphate, fructose 6-phosphate, fructose 1,6-bisphosphate, thiamin pyrophosphate, phosphoribosylpyrophosphate, ADP or ATP. Acid- and alkaline-phosphatase activities were observed with naphthyl phosphates as substrates, but they did not have the same electrophoretic mobility on gels as the PPase activity. U. urealyticum PPase was inhibited by oxidized glutathione, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, phenylglyoxal, p-chloromercuribenzoic acid, Mn2+, Zn2+ and Ca2+. Neither reduced glutathione, L-cysteine nor Co2+ enhanced activity. PPi can act as a substrate or regulator of certain metabolic reactions, and PPi metabolism can function in bacterial bioenergetics; its role in ureaplasmas is presently unclear.

Cations, Divalent↗

PubMed1977

Thiamine deficiency in fulminant hepatic failure and effects of supplementation.

Nine out of 24 patients with acute hepatocellular necrosis leading to fulminant hepatic failure showed biochemical evidence of thiamine deficiency early in the course of their illness, probably as a result of inadequate intake of the vitamin. This was corrected by twice daily administration of intravenous vitamin supplements containing thiamine hydrochloride (100 mg b.d.). These studies indicate that conversion of thiamine hydrochloride to its biologically active co-enzyme form, thiamine pyrophosphate, is possible even in the presence of severe acute hepatocellular necrosis, and it is suggested that supplements of the vitamin should be included in the routine management of patients with acute hepatic failure.

Acute Disease↗

PubMed1997

Characterization of thiI, a new gene involved in thiazole biosynthesis in Salmonella typhimurium.

Thiamine pyrophosphate (TPP) is a required cofactor in Salmonella typhimurium that is generated de novo by the condensation of 4-amino-5-hydroxymethyl pyrimidine (HMP) pyrophosphate and 4-methyl-5-(beta-hydroxyethyl)-thiazole (THZ) monophosphate. The THZ and HMP moieties are independently synthesized, and labeling studies have demonstrated probable metabolic precursors to both. We present herein the initial characterization of thiI, a gene required for THZ synthesis. We show that thiI is a 1,449-bp open reading frame located at minute 9.65 on the S. typhimurium chromosome and that it encodes a 483-amino-acid protein with a predicted molecular mass of 55 kDa. Unlike genes in the thiamine biosynthetic operon at minute 90, thiI is not transcriptionally regulated by TPP.

Amino Acid Sequence↗

PubMed2002

Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency.

Pyruvate dehydrogenase complex (PDHC) deficiency is a major cause of congenital lactic acidemia in children. PDHC catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment was effective for some patients with PDHC deficiency. We reexamined 30 patients with congenital lactic acidemia of unknown origin who had normal PDHC activity in their cultured fibroblasts using a routine assay with a high (0.4 mM) thiamine pyrophosphate (TPP) concentration. We measured the activity of PDHC in the presence of a low (1x10(-4) mM) TPP concentration, and analyzed for mutations in the E1alpha subunit gene. Three males had low PDHC activity in the presence of 1x10(-4) mM TPP. The DNA sequence of these three patients' X-linked E1alpha subunit revealed a substitution of alanine for valine at position 71 (V71A) in exon 3, phenylalanine for cysteine at position 101 (C101F) in exon 4, and glycine for arginine at position 263 (R263G) in exon 8, respectively. Thiamine treatment was effective in these three patients. Therefore, they had a thiamine-responsive PDHC deficiency due to a point mutation in the E1alpha subunit gene. PDHC activity should be measured at a low TPP concentration to detect thiamine-responsive PDHC deficiency so that thiamine treatment can be initiated as soon as possible.

Acidosis, Lactic↗

PubMed1982

Studies of the flavin adenine dinucleotide binding region in Escherichia coli pyruvate oxidase.

Experiments have been performed to probe the flavin adenine dinucleotide (FAD) binding region in Escherichia coli pyruvate oxidase. This enzyme functions as a membrane-associated flavoprotein coupled to the aerobic E. coli respiratory chain. The FAD moiety is noncovalently bound to pyruvate oxidase and can be removed reversibly to form apopyruvate oxidase. The addition of free FAD to apoenzyme results in the stoichiometric re-formation of the active flavoprotein. Using this technique, synthetic analogs of FAD were substituted in the flavin binding site and used as structural probes. Spectral analysis indicates that the benzoquinoid forms of 8-mercapto-FAD and 6-hydroxy-FAD are stabilized in the enzyme-binding site. This is consistent with the fact that the native flavoprotein forms a red (anion) radical upon photoreduction. These data suggest that the isoalloxazine ring may be poised for reduction via position N-5 by a carbanionic intermediate. The alpha-carbanion of hydroxyethylthiamin pyrophosphate, formed following the decarboxylation of pyruvate, is a likely candidate. The highly resolved visible spectrum of the native flavoprotein suggests that the flavin is buried in a hydrophobic environment. Reactivity studies using 8-chloro-FAD-pyruvate oxidase and 2-thio-FAD-pyruvate oxidase suggest that the C-8 position and C-2 position of the isoalloxazine ring may not be accessible to the solvent. Spectral perturbations observed with 6-hydroxy-FAD-pyruvate oxidase indicate, however, that the isoalloxazine C-6 position may be located near the binding site for the cofactor thiamin pyrophosphate. Restrictions to the accessibility of the active site of the enzyme are suggested by the fact that sulfite does not form an adduct with the flavin in the native enzyme.

Binding Sites↗

PubMedDate not supplied

Evaluation of a clinical screening instrument to identify states of thiamine deficiency in inpatients with severe alcohol dependence syndrome.

AIMS: To develop a Thiamine Deficiency Questionnaire (TDQ), and to assess its reliability in the identification of Thiamine deficiency, in patients with severe alcohol dependence. METHODS: 58 severely alcohol dependent patients underwent socio-demographic, medical, psychiatric, and alcohol use assessment, including administration of the Thiamine Deficiency Questionnaire (TDQ). The Red Blood Cell Thiamine Pyrophosphate concentration provided the 'gold standard' to test the validity of the instrument. Univariate 2 x 2 diagnostic test tables and multivariate analysis were performed. RESULTS: A set of eight questionnaire items had an overall predictive power of 73.7%. Two of these were highly specific: 'missed meals due to lack of funds', and the clinical co-occurrence of medical conditions potentially related to poor nutrition. The Michigan Alcohol Screening Test and serum gamma glutamyl transferase were moderately predictive. CONCLUSIONS: Screening that combines socio-demographic, clinical and biological factors, and/or standardized questionnaires, could improve early recognition of thiamine deficiency.

Adult↗

PubMed2001

Molecular cloning of human thiamin pyrophosphokinase.

Thiamin pyrophosphokinase (TPK, EC 2.7.6.2) catalyses phosphorylation of thiamin to thiamin pyrophosphate, an active enzyme cofactor. Here we describe the cloning of complete human TPK1 cDNA from an adult liver library. Human TPK1 is 89% identical to murine TPK1 at the protein level. The gene maps to chromosome 7q34-36, consists of at least eight exons, and spans a distance at least of 420 kb. The mRNA of human TPK1 is highly expressed in testis, small intestine and kidney with lesser but detectable expression in brain, liver, placenta and spleen. The availability of the human TPK1 gene will provide another useful tool for studying the role of this enzyme in human thiamin metabolism and deficiency state.

Amino Acid Sequence↗