Transport of thiamine by brush‐border membrane vesicles from rat small intestine.

Casirola, D.; Ferrari, G.; Gastaldi, Giulia; Patrini, Cesare; Rindi, G.

doi:10.1113/jphysiol.1988.sp017045

Cited by 47 publications

(25 citation statements)

References 22 publications

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“…These concentrations, which are much lower than the apparent Km of the specific component, the saturable mechanism. This mechanism is predominantly involved also in the intestinal absorption of thiamine (Casirola et al, 1988), whose physiological intraluminal concentrations in man and rat are estimated to be usually less than 2 #mol/L (Hoyumpa et al, 1975;Sklan and Trostler, 1977). The lack of the specific component of thiamine transport in TRMA patients could alter considerably the cellular exchanges and absorption of thiamine and determine a state of vitamin deficiency, at least when food is the only source of thiamine intake.…”

Section: Discussionmentioning

confidence: 97%

Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia

Rindi

Casirola

Poggi

et al. 1991

J of Inher Metab Disea

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A 9-year study of thiamine metabolism and cellular transport was performed in two patients with thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and sensorineural deafness, in their relatives, and in age-matched controls from the same area. The ratios between the content of thiamine and that of its phosphoesters in erythrocytes were within the normal range, whereas the absolute values of thiamine and thiamine compounds were reduced by about 40% as compared to controls. Thiamine pyrophosphokinase activity was about 30% lower than in controls. Thiamine treatment restored the levels of thiamine and thiamine compounds to normal values, whereas kinase was unaffected. Both the saturable (specific, predominant at low, less than 2 mumol/L, physiological concentrations of thiamine) and the non-saturable component of thiamine transport were investigated. Erythrocytes and ghosts from patients exhibited no saturable component, this abnormality being specific for the patients and not shared by their parents. It is concluded that the cells from thiamine-responsive megaloblastic anaemia patients contain low levels of thiamine compounds, probably due to their inability to take up and retain physiological concentrations of thiamine, as a result of the lack of the saturable, specific component of transport and reduced thiamine pyrophosphokinase.

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Section: Discussionmentioning

confidence: 97%

Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia

Rindi

Casirola

Poggi

et al. 1991

J of Inher Metab Disea

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“…It exhibited a dual (saturable and nonsaturable) mechanism (Fig. 4), as shown also for small intestinal intact tissue and brush border vesicles (see Casirola et al, 1988), and for hepatic and cerebral tissue (Yoshioka, 1984;Patrini et al, 1988). The saturable component was especially important at low thiamin concentrations (<0.5/ZM), followed Michaelis-Menten kinetics, was sensitive to incubation temperature (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Without considering differences in animal species (rat and man), both types of membranes appear to transport thiamin by a similar dual mechanism (for vesicles see Casirola et al, 1988), which is saturable at low (physiological) concentrations and nonsaturable at higher concentrations. In both membranes the saturable component displays affinities for thiamin of the same order of magnitude and similar molecular specificities, being inhibited to approximately the same extent by unlabeled thiamin and some structural analogues.…”

Section: Discussionmentioning

confidence: 99%

Thiamin transport by human erythrocytes and ghosts

et al. 1990

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Thiamin transport in human erythrocytes and resealed pink ghosts was evaluated by incubating both preparations at 37 or 20 degrees C in the presence of [3H]-thiamin of high specific activity. The rate of uptake was consistently higher in erythrocytes than in ghosts. In both preparations, the time course of uptake was independent from the presence of Na+ and did not reach equilibrium after 60 min incubation. At concentrations below 0.5 microM and at 37 degrees C, thiamin was taken up predominantly by a saturable mechanism in both erythrocytes and ghosts. Apparent kinetic constants were: for erythrocytes, Km = 0.12, 0.11 and 0.10 microM and Jmax = 0.01, 0.02 and 0.03 pmol.microliter-1 intracellular water after 3, 15, and 30 min incubation times, respectively; for ghosts, Km = 0.16 and 0.51 microM and Jmax = 0.01 and 0.04 pmol.microliter-1 intracellular water after 15 and 30 min incubation times, respectively. At 20 degrees C, the saturable component disappeared in both preparations. Erythrocyte thiamin transport was not influenced by the presence of D-glucose or metabolic inhibitors. In both preparations, thiamin transport was inhibited competitively by unlabeled thiamin, pyrithiamin, amprolium and, to a lesser extent, oxythiamin, the inhibiting effect being always more marked in erythrocytes than in ghosts. Only approximately 20% of the thiamin taken up by erythrocytes was protein- (probably membrane-) bound. A similar proportion was esterified to thiamin pyrophosphate. Separate experiments using valinomycin and SCN- showed that the transport of thiamin, which is a cation at pH 7.4, is unaffected by changes in membrane potential in both preparations.

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“…To confirm the specificity of thiamine uptake by Caco-2 cells, two thiamine analogs, amprolium and oxythiamine (Casirola et al, 1988), were used. As indicated in Fig.…”

Section: Resultsmentioning

confidence: 99%

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

Zhang

Diamond

et al. 2014

Drug Metab Dispos

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The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.

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Transport of thiamine by brush‐border membrane vesicles from rat small intestine.

Cited by 47 publications

References 22 publications

Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia

Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia

Thiamin transport by human erythrocytes and ghosts

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

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