Substances with antithiamin activity are fairly common in nature and include structurally similar antagonists as well as structure-altering antagonists. The synthetic compounds pyrithiamin, oxythiamin, and amprolium (an anticoccidial) are structurally similar antagonists. Their mode of action is competitive inhibition, interfering with thiamin at different points in metabolism. Pyrithiamin blocks the esterification of thiamin with phosphoric acid, resulting in inhibition of the thiamin coenzyme cocarboxylase. Oxythiamin competitively inhibits thiamin's binding to the carboxylase complex, blocking important metabolic reactions. Amprolium inhibits intestinal absorption of thiamin and also blocks phosphorylation of the vitamin (McDowell, 2000). Sulfur has been shown to be antagonistic to thiamin enzymes. The sulfite ion has been shown to cleave thiamin from enzymes at the methylene bridge and analytically, will imitate thiaminase. Sulfate increases thiamin-destroying activity in the rumen contents and the destructive mechanism involves thermolabile factor(s); however, the ruminal synthesis of thiamin is not affected by sulfate (Olkowski et al., 1993). Tall fescue (Festuca arundinacea Schreb.) toxicosis resembles diseases caused by elevated rumen thiaminase activity (Lauriault et al., 1990).
Thiaminase activity destroys thiamin by altering the structure of the vitamin. The disease "Chastek paralysis" in foxes and other animals fed certain types of raw fish results from a thiaminase that splits the thiamin molecule into two components, thus inactivating it. Since thiaminase is unstable to heat, the problem can be avoided by cooking the fish at 83°C for at least five minutes. Many different kinds of fish contain thiaminase, with thiamin deficiency being reported in penguins, seals, and dolphins fed primarily fish diets in zoos (Maynard et al., 1979). Thiaminase is found mainly in herrings, sprats, stints, and various carp species, a total of some 50 species, most of which live in fresh water. Wild aquatic animals apparently do not suffer thiamin deficiency even though they eat a diet primarily of fish, because fish must undergo some putrefaction to release the enzyme (Evans, 1975). In vitro and in vivo experiments have shown that 1 kg of fish can destroy up to 25 mg thiamin. This degradation takes place within the first 30 minutes after ingestion, when still in the stomach. Certain microorganisms (bacteria and molds) and plants (bracken fern) have been shown to produce thiaminases. A disease in horses known as "bracken fern poisoning" results from antagonism to thiamin.
Two types of thiaminase enzymes have been described–I and II. Thiaminase I substitutes a new base for the thiazole ring. This leads to less thiamin, but it also results in thiamin analogs consisting of the pyrimidine ring of the original thiamin and another ring from the "cosubstrate." This thiamin analog may then be absorbed and possibly inhibit thiamin-requiring reactions (Frye et al., 1991). Thiaminase II simply cleaves the vitamin at the methylene bridge between the thiazole and the pyrimidine rings.
Thiamin appears to be readily digested and released from naturally occurring sources. A precondition for normal absorption of thiamin is sufficient production of stomach hydrochloric acid. Phosphoric acid esters of thiamin are split in the intestine. The free thiamin formed is soluble in water and easily absorbed, especially in the jejunum. The mechanism of thiamin absorption is not yet fully understood, but apparently both active transport and simple diffusion are involved. At low concentrations, there is an active sodium-dependent transport of thiamin against the electrochemical potential, whereas at high concentrations, it diffuses passively through the intestinal wall. Thiamin synthesized by gut microflora in the cecum or large intestine is largely unavailable to the animal except by coprophagy. The horse can, however, absorb thiamin from the cecum. Ruminants can also absorb free thiamin from the rumen, but the rumen wall is not permeable for bound thiamin or for thiamin contained in rumen microorganisms.
Specific proteins (transporters and carriers) in the cell membrane have binding sites for thiamin, allowing it to be solubilized within the cell membrane. This permits the vitamin to pass through the membrane and ultimately reach the aqueous environment on the other side (Rose, 1990). Absorbed thiamin is transported via the portal vein to the liver with the carrier plasma protein. Thiamin is efficiently transferred to the fetus.
Thiamin phosphorylation can take place in most tissues but particularly in the liver. Four-fifths of thiamin in animals is phosphorylated in liver under the action of ATP to form the metabolically active enzyme form thiamin pyrophosphate (TPP or cocarboxylase). Of total body thiamin, about 80% is TPP, about 10% is thiamin triphosphate (TTP), and the remainder is thiamin monophosphate (TMP) and free thiamin.
Although thiamin is readily absorbed and transported to cells throughout the body, it is not stored to any great extent. The thiamin content in individual organs varies considerably and the vitamin is preferentially retained in organs with a high metabolic activity. During deficiencies, thiamin is retained in greatest quantities in major organs such as the liver, heart, brain and kidneys. Although liver and kidney tissues have the highest thiamin concentrations, approximately one-half of the total thiamin body stores are present in muscle tissue (Tanphaichir, 1976). Thiamin, however, is one of the most poorly stored vitamins. Most mammals on a thiamin-deficient diet will exhaust their body stores within one to two weeks (Ensminger et al., 1983).
Thiamin intakes in excess of current needs are rapidly excreted. Absorbed thiamin is excreted in both urine and feces, with small quantities excreted in sweat. Fecal thiamin may originate from feed, synthesis by microorganisms or endogenous sources (i.e., via bile or excretion through the mucosa of the large intestine). When thiamin is administered in large doses, urinary excretion first increases then reaches a saturation level, and with additional thiamin, the fecal concentration increases considerably (Bräunlich and Zintzen, 1976).
