The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity.

Decreased transketolase activity is an unexplained characteristic of patients with end-stage renal disease and is linked to impaired metabolic and immune function. Here we describe the discovery of a link to impaired functional activity of thiamine pyrophosphate cofactor through the presence, accumulation, and pyrophosphorylation of the thiamine antimetabolite oxythiamine in renal failure. Plasma oxythiamine was significantly increased by 4-fold in patients receiving continuous ambulatory peritoneal dialysis and 15-fold in patients receiving hemodialysis immediately before the dialysis session (healthy individuals, 0.18 [0.11-0.22] nM); continuous ambulatory peritoneal dialysis patients, 0.64 [0.48-0.94] nM; and hemodialysis patients (2.73 [1.52-5.76] nM). Oxythiamine was converted to the transketolase inhibitor oxythiamine pyrophosphate. The red blood cell oxythiamine pyrophosphate concentration was significantly increased by 4-fold in hemodialysis (healthy individuals, 15.9 nM and hemodialysis patients, 66.1 nM). This accounted for the significant concomitant 41% loss of transketolase activity (mU/mg hemoglobin) from 0.410 in healthy individuals to 0.240 in hemodialysis patients. This may be corrected by displacement with excess thiamine pyrophosphate and explain lifting of decreased transketolase activity by high-dose thiamine supplementation in previous studies. Oxythiamine is likely of dietary origin through cooking of acidic thiamine-containing foods. Experimentally, trace levels of oxythiamine were not formed from thiamine degradation under physiologic conditions but rather under acidic conditions at 100(°)C. Thus, monitoring of the plasma oxythiamine concentration in renal failure and implementation of high-dose thiamine supplements to counter it may help improve the clinical outcome of patients with renal failure.

Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle.

Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxythiamine (OT) was observed in several in vitro and in vivo tumor models. Here, we demonstrate that pentose cycle (PC) inhibitors, OT and dehydroepiandrosterone (DHEA), efficiently regulate the cell cycle and tumor proliferation processes. Increasing doses of OT or DHEA were administered by daily intraperitoneal injections to Ehrlich's ascites tumor hosting mice for 4 days. The tumor cell number and their cycle phase distribution profile were determined by DNA flow histograms. Tumors showed a dose dependent increase in their G0-G1 cell populations after both OT and DHEA treatment and a simultaneous decrease in cells advancing to the S and G2-M cell cycle phases. This effect of PC inhibitors was significant, OT was more effective than DHEA, both drugs acted synergistically in combination and no signs of direct cell or host toxicity were observed. Direct inhibition of PC reactions causes a G1 cell cycle arrest similar to that of 2-deoxyglucose treatment. However, no interference with cell energy production and cell toxicity is observed. PC inhibitors, specifically ones targeting TK, introduce a new target site for the development of future cancer therapies to inhibit glucose utilizing pathways selectively for nucleic acid production.

[Advantages of oxythiamine bromide as a specific inhibitor of activity of thiamine-dependent enzymes]. / Preimushchestva oksitiaminbromida kak spetsificheskogo ingibitora aktivnosti tiaminzavisimykh fermentov.

Production of hydrogen bromide salt of hydroxythiamine (Ht. HBr) from thiamine bromide was developed its toxic and inhibitory properties towards transketolase and pyruvate dehydrogenase were studied as compared with commercial preparation hydroxythiamine chloride (HT. HCl). As compared with HT. HCl, synthesis of HT. HBr was more simple, the higher yield and purity of the end product were achieved. At the same time, the preparation was less toxic and exhibited the antivitaminous activity similar to the commercial chloride form.

[Characteristics of carbohydrate metabolism in the rat liver in thiamine deficiency]. / Osobennosti obmena uglevodov v pecheni krys pri nedostatochnosti tiamina.

Thiamine deficiency in rats induced by oxythiamine is accompanied by an increase in the free NADP+/NADPH ratio in liver tissue, which results in multifold stimulation of the metabolite flux in the oxidation branch of the pentose cycle. The increase in the intracellular concentrations of isocitrate and alpha-ketoglutarate with a simultaneous decrease of malate in the liver of vitamin-deficient rats points to the inhibition of alpha-ketoglutarate dehydrogenase responsible for the anomalous metabolism under conditions of thiamine deficiency. The decrease of the functional activity of the tricarboxylic acid cycle is concomitant with the activation of conversions in the oxidation branch of the pentose cycle, glucuronate and glycolytic pathways of carbohydrate metabolism, which is directed at eliminating the energy deficiency in rats with B1-hypovitaminosis.

[Posttraumatic regeneration of the skeletal muscles in certain forms of hypovitaminosis B1]. / Posttravmaticheskaia regeneratsiia skeletnykh myshts pri nekotorykh formakh gipovitaminoza B1.

Light microscopy was employed to study the development of posttraumatic aseptic inflammation and subsequent regeneration in the affected musculus soleus in different patterns of hypovitaminosis B1. Alimentary deficiency of thiamine entailed pronounced retardation of the post-traumatic inflammation. The growth of macrophage density and formation of the pool of the regenerating cells were also retarded. On day 21 the regeneration pool showed an elevated content of the connective tissue. During long-term administration of oxythiamine in a dose of 10 mg/kg with a 12-hour interval, the development of the inflammatory response was marked by similar alterations, but the formation of muscle fibers and connective tissue proceeded more uniformly. A single administration of oxythiamine in a dose of 200 mg/kg did not bring about any substantial impairment of the early stages of regeneration. The alterations observed can be associated with different degree of inhibition of the activity of TDF-containing enzymes and derangement of the function of the nervous system.

[Transketolase inhibitors based on disulfide derivatives of oxythiamine with branched hydrocarbon chains]. / Ingibitory transketolazy na osnove disul'fidnykh proizvodnykh oksitiamina s razvetvlennymi uglevodorodnymi tsepiami.

The experiments on mice have shown that oxythiamine disulphide derivatives with the branched hydrocarbon chains are less toxic in the organism as compared to oxythiamine and corresponding disulphides with the unbranched hydrocarbon chains and also induce a more pronounced inhibition of transketolase in the liver and other tissues. It is found that under the effect of the above substances the recovery of enzymic activity is slower than in the case with the oxythiamine application.

[Synthesis of nucleic RNA in hydroxythiamine-induced vitamin B1 deficiency]. / Sintez iadernykh RNK pri vyzvannoi oksitiaminom nedostatochnosti vitamina B1.

24 hours after administration of hydroxythiamine (vitamin B1 antimetabolite) in a dose of 40 mg per 100 g of body weight, the incorporation of (2(14)C)-orotic acid and (methyl-14C)-methionine into total nuclear RNA decreases. The content of RNA and the specific radioactivity of cytoplasmic UTP and methionine pools remain unchanged. Thermal phenol fractionation of nuclear RNA reveals a decrease in a predominant synthesis of nucleolar RNA, while that of heterogeneous nuclear RNA, tRNA, and 5S-RNA remains unaffected.