Substances with anti-thiamin 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 co-carboxylase. 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. Tall fescue (Festuca arundinacea Schreb.) toxicosis resembles diseases caused by elevated rumen thiaminase activity (Lauriault et al., 1990).
Thiaminase alters the structure of the vitamin. The disease "Chastek paralysis" in foxes and other animals fed certain types of raw fish results from a thiaminase. Since thiaminase is inactivated by heat, the problem can be avoided by cooking the fish at 83†C for at least five minutes. Certain microorganisms (bacteria and molds) and plants (bracken fern) produce thiaminases and can produce toxicity in animals.
Two types of thiaminase enzymes have been described. Thiaminase I substitutes a different base for the thiazole ring, which produces a thiamin analog in addition to reducing thiamin supply. The thiamin analog may then be absorbed and possibly inhibit thiamin-requiring enzyme reactions (Frye et al., 1991). In contrast, thiaminase II simply cleaves thiamin at the methylene bridge between the thiazole and the pyrimidine rings. More detailed reviews of the role of thiaminases in induced thiamin deficiency in ruminants are available (Frye et al., 1991; Harmeyer and Kollenkirchen, 1989).
Thiamin appears to be readily digested and absorbed from naturally occurring sources. A precondition for normal absorption of thiamin is sufficient production of hydrochloric acid in the stomach. Phosphoric acid esters of thiamin are hydrolyzed in the small intestine. The free thiamin formed is water soluble 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 (Braunlich and Zintzen, 1976; Gubler, 1991). At low concentrations, there is an active sodium-dependent transport of thiamin against the electrochemical potential, whereas at high concentrations (>2 µM), absorption occurs by diffusion across the intestinal wall. Specific thiamin-binding proteins in the cell membrane allow thiamin to be solubilized within the cell membrane. This permits passage through the membrane for release into the aqueous environment of the cytosol (Rose, 1996). Thiamin is transported to the liver via the portal vein, bound to a carrier protein. Up to 90% of whole blood thiamin is concentrated in the erythrocytes and leukocytes (Gubler, 1991). Red blood cells and leukocytes accumulate thiamin in part due to their dependence on the pentose pathway and glycolysis.
Thiamin phosphorylation takes place in most tissues, but particularly in the liver. Eighty percent of thiamin in animals is phosphorylated in the liver by thiamin pyrophosokinase, an ATP-requiring enzyme. The metabolically active, thiamin pyrophosphate (TPP, or co-carboxylase) is formed. Of total body thiamin, about 80% is found as TPP, 10% as thiamin triphosphate (TTP) and the remaining 10% as 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, spleen and kidney. Although liver and kidney tissues have the highest thiamin concentrations, approximately one-half of the total thiamin body stores are present in muscle tissue (Tanphaichair, 1976). Thiamin, however, is one of the most poorly stored vitamins. Most mammals fed a thiamin-deficient diet will exhaust their body stores within one to two weeks (Ensminger et al., 1990).
Thiamin intakes in excess of immediate needs are rapidly excreted. Absorbed thiamin is excreted in both urine and feces, with small quantities excreted in sweat. Fecal thiamin originates 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 increases first to a saturation level, followed by a progressive increase in fecal excretion (Braunlich and Zintzen, 1976).
