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At least 19 recordsLinked to original sources
PubMed1968

Metabolism of pyrithiamine by the pyrithiamine-requiring mutant of Staphylococcus aureus.

1. A mutant strain of Staphylococcus aureus that requires pyrithiamine for its optimum growth was found to utilize pyrithiamine during the exponential phase of growth. 2. Pyrithiamine was deaminated by the organism to form oxypyrithiamine, the reaction being enzymic with no cofactor requirement. 3. On prolonged incubation of S. aureus A cultures, the concentration of deaminating enzyme increased in the culture broth, from which pyrithiamine-deaminating enzyme could be isolated by solvent fractionation. 4. Oxypyrithiamine is not a competitive analogue of thiamine although it inhibited the growth of the parent strain of S. aureus; the inhibition index of this compound, however, was lower than that of pyrithiamine.

Antimetabolites↗
PubMed1985

Involvement of sulfhydryl groups in the inhibition of brain (Na+ + K+)-ATPase by pyrithiamin.

Brain (Na+ + K+)-ATPase was protected by low concentrations of GSH from the inhibitory effect of pyrithiamin. The possible involvement of sulfhydryl groups in the inhibition was then studied by comparing the effect of pyrithiamin with that of N-ethylmaleimide on the enzyme. The treatment of rat brain (Na+ + K+)-ATPase with thesee inhibitors caused a significant decrease in reactivity of the enzyme to N-ethyl[3H]maleimide. N-Ethylmaleimide, like pyrithiamin, inhibited the partial reactions of (Na+ + K+)-ATPase system in parallel with the inhibition of the overall reaction. An SDS-polyacrylamide gel electrophoresis procedure indicated that pyrithiamin and N-ethylmaleimide inhibited Na+-dependent phosphorylation of the alpha(+) form of rat brain (Na+ + K+)-ATPase more than that of alpha, though the selectivity for the alpha(+) seemed to be higher with the former inhibitor than in the latter. The treatment also decreased sensitivity of the enzyme to ouabain inhibition. However, pyrithiamin- and N-ethylmaleimide-induced inactivations of the enzyme differed in the efficacy of GSH for protection and in the effect of the kind of ligands present during the reaction. Furthermore, pyrithiamin did not appear to interact directly with sulfhydryl groups, but caused the formation of disulfide in bovine brain (Na+ + K+)-ATPase. In contrast to N-ethylmaleimide, pyrithiamin did not affect the sulfhydryl-enzymes such as alcohol dehydrogenase and L-alanine dehydrogenase. It is concluded that pyrithiamin modifies the functional sulfhydryl groups of brain (Na+ + K+)-ATPase in a way different from N-ethylmaleimide and causes a structural change and inactivation of the enzyme.

Animals↗
PubMed2005

Pyrithiamine as a substrate for thiamine pyrophosphokinase.

Thiamine pyrophosphokinase transfers a pyrophosphate group from a nucleoside triphosphate, such as ATP, to the hydroxyl group of thiamine to produce thiamine pyrophosphate. Deficiencies in thiamine can result in the development of the neurological disorder Wernicke-Korsakoff Syndrome as well as the potentially fatal cardiovascular disease wet beriberi. Pyrithiamine is an inhibitor of thiamine metabolism that induces neurological symptoms similar to that of Wernicke-Korsakoff Syndrome in animals. However, the mechanism by which pyrithiamine interferes with cellular thiamine phosphoester homeostasis is not entirely clear. We used kinetic assays coupled with mass spectrometry of the reaction products and x-ray crystallography of an equilibrium reaction mixture of thiamine pyrophosphokinase, pyrithiamine, and Mg2+/ATP to elucidate the mechanism by which pyrithiamine inhibits the enzymatic production of thiamine pyrophosphate. Three lines of evidence support the ability of thiamine pyrophosphokinase to form pyrithiamine pyrophosphate. First, a coupled enzyme assay clearly demonstrated the ability of thiamine pyrophosphokinase to produce AMP when pyrithiamine was used as substrate. Second, an analysis of the reaction mixture by mass spectrometry directly identified pyrithiamine pyrophosphate in the reaction mixture. Last, the structure of thiamine pyrophosphokinase crystallized from an equilibrium substrate/product mixture shows clear electron density for pyrithiamine pyrophosphate bound in the enzyme active site. This structure also provides the first clear picture of the binding pocket for the nucleoside triphosphate and permits the first detailed understanding of the catalytic requirements for catalysis in this enzyme.

Adenosine Monophosphate↗
PubMed1984

Specific inactivation of alpha (+) molecular form of (Na+ + K+)-ATPase by pyrithiamin.

We have recently reported that pyrithiamin inhibits the activity of (Na+ + K+)-ATPase derived from neuronal but not non-neuronal tissue. In view of the recent demonstration that there are two molecular forms of (Na+ + K+)-ATPase in brain, the present study has examined which form of the enzyme is selectively inhibited by pyrithiamin. Experiments with sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the treatment with pyrithiamin decreased the phosphorylation by [gamma-32P]ATP of alpha (+) in a dose-dependent manner while it had little effect on that of alpha. Furthermore, the treatment with pyrithiamin changed the sensitivity of the enzyme to ouabain and N-ethylmaleimide. The specificity of the action of pyrithiamin for alpha (+) was further examined in the developing rat brain (Na+ + K+)-ATPases and peripheral (Na+ + K+)-ATPases from various animals. The molecular form of rat brain (Na+ + K+)-ATPase was primarily alpha on the 14th day of gestation, while it was mainly alpha (+) on the 18th day of gestation and postnatal age. The enzyme from 14-day fetal rat brain was resistant to pyrithiamin inhibition more than other brain enzymes. In cardiac and renal (Na+ + K+)-ATPases from various animals, only the alpha molecular form was found except for dog cardiac preparation which contained alpha (+) and alpha. Pyrithiamin inhibited dog cardiac enzyme activity, while it exerted only minimal inhibition on other peripheral enzymes. It is concluded that pyrithiamin selectively inactivates the alpha (+) molecular form of (Na+ + K+)-ATPase.

Animals↗
PubMed1979

Pyrithiamin shortens ethanol-induced narcosis and increases voluntary ethanol drinking in rats.

To investigate the role of thiamin deficiency in increasing voluntary ethanol intake in rats the effect of ethanol on the central nervous system was studied by measuring the duration of ethanol narcosis in pyrithiamin-treated rats. The duration of ethanol-induced narcosis was significantly shorter and blood ethanol concentration at the moment of righting reflex recovery was higher in pyrithiamin-treated rats than in controls. Thus, the shorter ethanol narcosis of pyrithiamin-treated rats was not a result of a change in ethanol metabolism but rather suggests changes in the central effects of ethanol. Treatment with thiamin increased the duration of ethanol narcosis to the initial level in rats pretreated with pyrithiamin. During the same pyrithiamin treatment as used for the narcosis test voluntary ethanol intake of rats was higher than during optimal treatment by thiamin. The results suggest that there might be a decrease in central sensitivity to ethanol in pyrithiamin treated rats, which may have a role in increasing their voluntary ethanol drinking.

Alcohol Drinking↗
PubMedDate not supplied

Effects of pyrithiamin and oxythiamin on acetylcholine levels and utilization in rat brain.

Regional cerebral acetylcholine (ACh) levels and utilization rate were assessed in vivo in rats rendered thiamin deficient using the thiamin antagonists pyrithiamin or oxythiamin. ACh levels were significantly reduced in all brain regions of pyrithiamin treated rats and in the medulla-pons and striatum of oxythiamin treated rats compared to controls. ACh utilization was significantly reduced in the midbrain, striatum and hippocampus of pyrithiamin treated rats, but was reduced only in the striatum of oxythiamin treated rats compared to controls. Thus, there are some reductions in ACh levels and utilization that are unique to pyrithiamin induced deficiency and as such are distinct from oxythiamin/undernutrition related reductions. Since only pyrithiamin produces neurological symptoms, its unique ACh effects may be related to these symptoms.

Acetylcholine↗
PubMed1983

Inhibition of neuronal sodium and potassium ion activated adenosinetriphosphatase by pyrithiamin.

Since one of the electrophysiological effects of pyrithiamin, an antimetabolite of thiamin, suggested an interference with sodium pump mechanisms, the effect of pyrithiamin on Na+,K+-ATPase was investigated. We found that whereas preincubation of the antimetabolite with nonneuronal preparations of Na+,K+-ATPase produced only minimal inhibition, the enzyme derived from brain preparations was markedly inhibited. This inhibition could be prevented by thiamin but not reversed. The kinetic study showed that pyrithiamin acts in a noncompetitive manner with respect to the activation of the enzyme by ATP, Na+, and K+. Pyrithiamin inhibited Na+-dependent phosphorylation and K+-stimulated phosphatase as well as ouabain binding, and these inhibitions were parallel with that of the overall Na+,K+-ATPase reaction. In addition, the antimetabolite caused a significant change in the turbidity of the enzyme suspension. The results suggest that pyrithiamin may induce a structural change of the enzyme complex.

Animals↗
PubMed1988

Long-lasting changes in regional brain amino acids and monoamines in recovered pyrithiamine treated rats.

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine + a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were significantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.

Amino Acids↗
PubMed1984

Effect of pyrithiamine treatment on potassium ion fluxes in rat cortical slices.

The effect of thiamine deficiency on energy-requiring processes in brain tissue was studied by comparing cortical slices prepared from control and pyrithiamine-treated rats. Veratridine was used to stimulate energy metabolism by opening voltage-sensitive sodium channels resulting in enhanced Na+/K+ pumping; subsequent tetrodotoxin addition closed the sodium channels. Pyrithiamine-treated slices showed both lower basal and veratridine-stimulated respiration rates compared to control slices. K+ was released from the tissue upon addition of veratridine and was taken up again upon addition of tetrodotoxin. The movement of K+ was monitored directly with a K+-sensitive electrode as well as by measuring the rubidium diffusion potential. There was no difference between control and pyrithiamine-treated slices in K+ fluxes in response to veratridine and tetrodotoxin. The extent of reuptake of K+ upon tetrodotoxin addition was inversely related to the extracellular Ca2+ concentration and to the incubation temperature. Veratridine resulted in a marked decrease in tissue levels of ATP and creatine phosphate; these levels remained quite low upon tetrodotoxin addition. Despite the different respiration rates, control and pyrithiamine-treated slices showed the same ATP and creatine phosphate levels in response to veratridine and tetrodotoxin.

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↗
PubMed1962

Pyrithiamine adaptation of Staphylococcus aureus. I. Adaptation and carbohydrate utilization.

Das, S. K. (University of Calcutta, Calcutta, India) and G. C. Chatterjee. Pyrithiamine adaptation of Staphylococcus aureus. I. Adaptation and carbohydrate utilization. J. Bacteriol. 83:1251-1259. 1962.-Staphylococcus aureus has been adapted to pyrithiamine, a thiamine analogue; as a result of this adaptation, the color of the pigment of the organism changes from orange-yellow to lemon-yellow. The adaptation is reversible; the adapted strain will revert after repeated subculture in a medium containing thiamine and no pyrithiamine. Of the major biochemical alterations resulting from adaptation, severe depression in glucose utilization and simultaneous stimulation of acetate utilization have been noticed. The effect of metabolic inhibitors on the utilization of glucose and acetate has also been studied. By measuring the rate of formation of C(14)O(2) from glucose-1-C(14) and glucose-6-C(14), it has been observed that the reduction in C(14)O(2) formation from glucose-1-C(14) by the adapted organism is much more than that obtained from glucose-6-C(14), causing thereby a decreased metabolic ratio of these two substrates after such adaptation. Relative to the normal strain, the adapted strain utilizes acetate-C(14) at a much faster rate, both in the formation of C(14)O(2) and also in the incorporation of C(14) into the protein and lipid fractions; the rate of formation of C(14)O(2) from pyruvate-1-C(14) is not greatly altered. It has been postulated that there is a partial blocking of the pentose phosphate cycle, because of the lowered glucose-1-C(14) utilization, and simultaneous stimulation of the tricarboxylic acid cycle; or perhaps the initiation of some other route after pyrithiamine adaptation would account for the great increase in acetate utilization.

Acclimatization↗
PubMed1963

PYRITHIAMINE ADAPTATION OF STAPHYLOCOCCUS AUREUS. II. TRICARBOXYLIC ACID CYCLE AND RELATED ENZYMES.

Das, S. K. (Calcutta University, Calcutta, India), and G. C. Chatterjee. Pyrithiamine adaptation of Staphylococcus aureus. II. Tricarboxylic acid cycle and related enzymes. J. Bacteriol. 86:1157-1164. 1963.-Evidence for the stimulated operation of the tricarboxylic acid cycle in Staphylococcus aureus after pyrithiamine adaptation is presented. In the cell-free extracts, isocitric, glutamic, malic, and succinic dehydrogenases and catalase were found to be stimulated after the adaptation of S. aureus to pyrithiamine. Besides such stimulation, the appearance of isocitratase and malate synthetase in the adapted strain supports the appearance of the glyoxalate bypass after such adaptation. There is little change in the activities of reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and diaphorase. Lactic dehydrogenase, NADH-cytochrome c reductase, and NADPH-cytochrome c reductase could not be demonstrated either in the normal or in the pyrithiamine-adapted S. aureus. These observations support the postulation that there is a stimulation in the tricarboxylic acid cycle and can account for the very marked stimulation in the utilization of acetate by the organism after adaptation.

Acclimatization↗
PubMed1981

[Effects of repeated administration of pyrithiamine and oxythiamine on timing behavior in rats (author's transl)].

Male Wistar rats were trained to hold down a lever for reinforcement with food pellets. No external stimulus signalled the end of the required duration. The minimum duration required was gradually raised to, and fixed at, 2 seconds. This was achieved in about 1-2 months. At the end of pre-drug training, the average response duration was 2.06 +/- 0.03 seconds in a daily 10-minute session. Daily injections of pyrithiamine, a thiamine analog which causes a rapid depletion of the brain vitamin, were given after the daily experimental session. The average response duration increased significantly by the 8th day of pyrithiamine treatment (2 mg/kg/day), without altering any other parameters examined. This pyrithiamine-induced change in duration, which was gradually diminished after the 14-day drug period, could be reversed with thiamine (2 doses of 5 mg/kg). On the other hand, oxythiamine did not cause an increase in duration over the 14 days of daily injections. The results obtained suggest that pyrithiamine exerted significant effects on discrimination of duration or internal timing mechanism in rats at the doses used, perhaps because of the depletion of the brain vitamin.

Animals↗
PubMed1975

[The influence of the antivitamine pyrithiamine on the metabolism of the thiamin-autotrophic Serratia marcescens].

A new method is described for the quantitative microbiological analysis of the thiamine analog pyrithiamine present in biological material. The method uses a mutant of Lactobacillus fermenti (ATCC 9338) stimulated by pyrithiamine. By this specific method it is found that Serratia marcescens is able to consume and to phosphorylate the antivitamine (presumably to pyrithiamine monophosphate). The uptake of the analog influences neither the generation time of Serratia marcescens nor the biomass of the culture, nor the total amounts of carbohydrate and protein within the cells. On the contrary, pyrithiamin stimulates the exponential death-rate k and decreases the quantity of neutral fats. The carbon source glycerol is consumed at a higher rate, which is paralleled by an increased total amount of pyruvate as well as by an increased biosynthesis of acetoin.

Acetoin↗
PubMed1975

Glycolytic metabolism in cultured cells of the nervous system. III. The effects of thiamine deficiency and pyrithiamine on the C-6 glioma and C-1300 neuroblastoma cell lines.

The effects of thiamine deficiency and of the antithiamine drug pyrithiamine on the C-6 glioma and the C-1300 neuroblastoma cell lines have been studied. Thiamine deficiency increased the doubling time of the neuroblastoma cells without affecting that of the glioma cells. Pyrithiamine prevented both cell lines from doubling even once. (hiamine deficiency had only slight effects on intracellular pyruvate and lactate levels or on efflux rates for the acids, but pyrithiamine treatment resulted in large increases in both the intracellular levels and the efflux in both cell lines. For comparison, the pyruvate and lactate levels in mouse brain were measured. The levels from thiamine-deficient mouse brain were essentially unchanged from controls while pyrithiamine treatment caused a significant elevation only of the pyruvate concentration.

Animals↗
PubMed1988

Reversible alterations of cerebral gamma-aminobutyric acid in pyrithiamine-treated rats: implications for the pathogenesis of Wernicke's encephalopathy.

Treatment of rats with the central thiamine antagonist, pyrithiamine, results in severe neurological symptoms such as loss of righting reflex. Measurement of gamma-aminobutyric acid (GABA) content of brain tissue from symptomatic pyrithiamine-treated (PT) rats revealed significant reductions in thalamus, cerebellum, and pons. GABA content of cerebral cortex, however, was unaltered. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were reduced in parallel with the GABA changes. On the other hand, activities of the GABA-synthetic enzyme glutamic acid decarboxylase (GAD) remained within normal limits, with the exception of a small but significant decrease in thalamus of symptomatic PT rats. Affinities and densities of high-affinity [3H]muscimol binding sites on crude cerebral membrane preparations from symptomatic PT rats were unchanged. Thiamine administration to symptomatic animals resulted in correction of abnormal righting reflexes and in normalization of decreased GABA levels and reduced alpha KGDH activities in cerebellum and pons. Thalamic GABA levels and alpha KGDH activities, on the other hand, remained significantly lower than normal. These results suggest that the reversible symptoms of pyrithiamine treatment may result from imparied GABA synthesis in cerebellum and pons of these animals. Similar mechanisms may play a role in the pathogenesis of the reversible symptoms of Wernicke's encephalopathy in man.

Animals↗
PubMed1982

Effect of a single, large dose injection of pyrithiamin on the thiamin deficiency of the mouse.

The effect of pyrithiamin on thiamin deficient mice was studied clinically and pathologically. Thiamin deficiency was produced in the mice fed with a thiamin deficient diet by a single injection of pyrithiamin (10 mg/kg, s.c.) on day 0 to produce a mild illness and on day 14 to produce a severe disorder. Clinically, the mild illness showed only Wooley-White sign and histologically, it was characterized by edema in the thalamus, mammillary bodies, and pontine tegmentum. The severe illness showed convulsion and multiple hemorrhages in the same area. This pyrithiamin-induced thiamin deficient animal model can also be useful for research on thiamin deficient encephalopathy.

Animals↗