Thiamine (vitamin B1) is a water-soluble vitamin and belongs to the group of B vitamins. Based on the observation by the Dutch physician Christiaan Eijkman at the end of the 19th century that beriberi-like symptoms occurred in chickens after they were fed hulled and polished rice, but not after they were given unhulled and unpolished rice or rice bran, thiamine is also known as the “antiberiberi vitamin.” After isolation of the beriberi protective substance from rice husks and naming of the vitamin as aneurin in 1926 by Jansen and Donath, the structural elucidation and synthesis of vitamin B1 by linking both ring structures was carried out in 1936 by Williams and Windaus, and the B vitamin was named thiamine. The thiamine molecule consists of a pyrimidine and thiazole ring linked by a methylene group. Thiamine itself does not find therapeutic application, but only their hydrophilic (water-soluble) salts, such as thiamine chloride hydrochloride, thiamine mononitrate, and thiamine disulfide, or their lipophilic (fat-soluble) derivatives (allithiamines), such as benfotiamine (S-benzoylthiamine-o-monophosphate; BTMP), bentiamine (dibenzoylthiamine), and fursultiamine (thiamine tetrahydrofurfuryl disulfide). Dry vitamin B1 is stable at 100 °C. Aqueous vitamin B1 solutions are most stable at pH < 5.5, but not in neutral or alkaline environments. Thiamine is both thermolabile (heat sensitive) and sensitive to light and oxidation, and exhibits high structural or constitutional specificity. Minor changes in molecular structure are associated with a reduction in vitamin efficacy, inefficacy, or, in certain cases, an antagonistic (opposite) mode of action. Thiamine antagonists, such as oxythiamine, pyrithiamine, and amprolium, can inhibit (inhibit) thiaminase I and II (thiamine-cleaving and -inactivating enzymes) and inhibit the binding of biologically active thiamine pyrophosphate (TPP; synonyms: Thiamine diphosphate (TDP), cocarboxylase) to its apoenzyme and competitively inhibit the decarboxylation (cleavage of a carbon dioxide (CO2) molecule) of 2-oxoacids, respectively. Infusion solutions containing sulfite (SO2) lead to complete degradation of vitamin B1.
Absorption
Thiamine is found in both plant and animal foods, but only in low concentrations. Whereas thiamine is present in free, nonphosphorylated form in plants, 80-85% of the B vitamin occurs in animal tissues as biologically active TPP and TDP, respectively, and 15-20% as thiamine monophosphate (TMP) and thiamine triphosphate (TTP). Phosphorylated vitamin B1 ingested with food is dephosphorylated by non-specific phosphatases of the intestinal wall (enzymatic removal of phosphate groups) and thus converted into an absorbable state. Absorption of free thiamine is highest in the jejunum (empty intestine), followed by the duodenum (duodenum) and ileum (ileum). Only small amounts are absorbed in the stomach and colon (large intestine). Intestinal absorption (uptake via the gut) of thiamine is subject to a dose-dependent dual mechanism. Physiological amounts of the B vitamin below a concentration of 2 µmol/l are absorbed by an energy-dependent sodium-mediated carrier mechanism. Thus, transport of vitamin B1 into intestinal mucosal (mucosal) cells is active and saturable. Structural analogues, such as pyrithiamine, can inhibit active vitamin B1 absorption by displacing thiamine from its transport proteins located in the apical (facing the interior of the intestine) cell membrane. The influence of alcohol or ethanol, on the other hand, consists in an inhibition of sodium–potassium adenosine triphosphatase (Na+/K+-ATPase; enzyme that catalyzes the transport of Na+ ions out of the cell and K+ ions into the cell by ATP cleavage) in the basolateral cell membrane (facing away from the interior of the intestine), resulting in the downregulation of the thiamine-specific transport proteins. Above a concentration of 2 µmol/l, absorption of vitamin B1 occurs by passive diffusion, which is neither sodium-dependent nor can be inhibited by thiamine antagonists or ethanol.As the applied (administered) dose increases, the percentage of absorbed thiamine decreases. This is due, on the one hand, to the downregulation of the transmembrane transport proteins for thiamine in the intestinal mucosa cells (mucosal cells) from a vitamin B1 dose > 2 µmol/l and, on the other hand, to the ineffectiveness of the passive absorption pathway compared with the active carrier-mediated transport mechanism. According to studies with orally administered radiolabeled thiamine, the absorption rate at an intake of 1 mg is ~ 50%, of 5 mg ~ 33%, of 20 mg ~ 25%, and of 50 mg ~ 5.3%. In total, only a maximum of 8-15 mg of vitamin B1 per day can be absorbed. Comparison of biopsies (tissue samples) of the intestinal mucosa of patients with and without thiamine deficiency showed significantly higher intestinal vitamin B1 absorption in the subjects with poor thiamine status. The increased absorption of vitamin B1 in the deficient state results from upregulation (upregulation) of the apical thiamine transporters in the intestinal mucosa cells (mucosal cells). Absorbed thiamine is partially phosphorylated in intestinal mucosal cells (mucosal cells) by cytosolic pyrophosphokinase with cleavage of adenosine triphosphate (ATP) to coenzymatically active TPP (enzymatic attachment of phosphate groups). In addition to the sodium-mediated carrier mechanism, intracellular pyrophosphokinase is also believed to be the rate-limiting step in the active transport of thiamine into and across the mucosa cell. Free and phosphorylated thiamine enters the liver via the portal vein, from where it is transported via the bloodstream to target organs and tissues according to their requirements.
Transport and distribution in the body
Vitamin B1 transport in whole blood occurs mainly in blood cells – 75% in erythrocytes (red blood cells) and 15% in leukocytes (white blood cells). Only 10% of vitamin B1 in the blood is transported plasmatically, primarily bound to albumin. The intake of high doses of vitamin B1 leads to the binding capacity being exceeded, so that excess thiamine is excreted. Total blood levels vary between 5-12 µg/dl. At the target organs and tissues, thiamine is taken up into the target cells and mitochondria (“energy power plants” of the cells) via a thiamine transporter with high affinity (binding strength). Due to the physiological importance of vitamin B1 in carbohydrate and energy metabolism, cardiac muscle (3-8 µg/g), kidney (2-6 µg/g), liver (2-8µg/g), brain (1-4 µg/g) and skeletal muscle in particular have high thiamine concentrations. In thiamine deficiency, due to upregulation (upregulation) of transmembrane transport proteins, the uptake of vitamin B1 into target cells is increased. Free thiamine can be phosphorylated to the biologically active TPP in all organs and tissues by intracellular pyrophosphokinase with ATP consumption and accumulation of two phosphate residues. Alcohol or ethanol prevents the activation of free thiamine to the coenzyme TPP by competitive inhibition of pyrophosphokinase. The transfer of a further phosphate group to TPP by means of a kinase with cleavage of ATP leads to TTP, which can be converted back to TPP, TMP or free, unphosphorylated thiamine under the action of phosphatases. While vitamin B1 is found in blood plasma, breast milk, and cerebrospinal fluid (affecting the brain and spinal cord) mainly in free form or as TMP, blood cells (leukocytes; erythrocytes) and tissues contain mainly TPP. For the intracellular coenzymatically active TPP, the cell membrane is impermeable (impermeable). TPP can only leave the cell after hydrolysis (cleavage by reaction with water) via TMP to free thiamine. Intracellular phosphorylation (enzymatic attachment of phosphate groups) and lowering of membrane permeability (membrane permeability) for phosphorylated thiamine ultimately serves as a protective mechanism to prevent vitamin B1 losses from physiological doses (1-2 mg/d). The total body stock of vitamin B1 in healthy individuals is 25-30 mg, of which approximately 40% is found in the muscles. A thiamine store in the narrower sense does not exist. Due to its function as a coenzyme, vitamin B1 is always associated (linked) with the corresponding enzyme and is only retained (retained by the kidney) to the extent that is currently required.The biological half-life of thiamine is relatively short and is reported to be 9.5-18.5 days in humans. The limited storage capacity and high turnover rate of the B vitamin necessitate a daily intake of sufficient amounts of thiamine to meet requirements, especially in cases of increased vitamin B1 consumption as a result of increased metabolism, such as during sports, heavy physical labor, within pregnancy and lactation, chronic alcohol abuse, and fever.
Excretion
Vitamin B1 excretion is dose-dependent. In the physiologic (normal for metabolism) range, approximately 25% of thiamine is eliminated renally (via the kidney). At high applied doses, excretion of vitamin B1 occurs almost completely via the kidney after tissue saturation, with a simultaneous increase in the proportion of thiamine excreted via the bile and of unabsorbed thiamine in the feces. This renal overflow effect is an expression of self-depression of non-renal clearance processes (excretion processes) as well as saturation of tubular reabsorption (reabsorption in the renal tubules). About 50% of thiamine is eliminated in free form or esterified with a sulfate group. The remaining 50 % are as yet unidentified metabolites as well as thiaminecarboxylic acid, methylthiazoleacetic acid and pyramine. The higher the vitamin B1 intake, the lower the metabolization and the greater the excretion of free, unchanged thiamine.
Allithiamine
Allithiamines, such as benfotiamine, bentiamine, and fursultiamine, are lipophilic (fat-soluble) thiamine derivatives that, according to the discovery by Fujiwara’s Japanese research group in the early 1950s, are formed spontaneously under physiological conditions by the combination of thiamine with allicin, the active ingredient in garlic and onions. In the allithiamine derivatives, the thiazole ring, which is essential for vitamin action, is open and the sulfur atom is substituted with a lipophilic group. Only after closure of the thiazole ring by compounds containing SH groups, such as cysteine and glutathione, in the intestinal mucosa cells (mucosal cells) and after phosporylation (enzymatic addition of phosphate groups) to the biologically active thiamine pyrophosphate in the target cells can the allithiamines exert their vitamin effect in the organism. Due to their apolar structure, allithiamines are subject to different absorption conditions than water-soluble thiamine derivatives, which are absorbed according to saturation kinetics in an energy- and sodium-dependent manner with the aid of a carrier mechanism. The uptake of allithiamines into the mucosa cells (mucosal cells) of the intestine occurs after prior dephosphorylation (removal of phosphate groups) by nonspecific phosphatases at the intestinal mucosa (intestinal mucosa) dose-proportionally by passive diffusion, whereby the allithiamines pass the intestinal absorption barrier faster and more easily compared to the water-soluble thiamine derivatives due to their better membrane permeability (membrane permeability). The bioavailability of lipophilic benfotiamine is about 5- to 10-fold higher than that of thiamine disulfide and thiamine mononitrate, respectively. In addition, allithiamines achieve higher levels of thiamine and TPP in whole blood, target organs and tissues after oral administration at comparatively low doses and are retained (retained) in the body longer. Hilbig and Rahmann (1998), who studied the tissue distribution and fate of radiolabeled benfotiamine and thiamine hydrochloride in blood and various organs, measured significantly higher radioactivities in all organs after benfotiamine administration, especially in liver and kidney. A 5- to 25-fold higher concentration of benfotiamine was found in the brain and muscles. In all other organs, the benfotiamine content was 10-40% higher than that of thiamine hydrochloride.
