Metabolic fate and mechanism of action of chloroethylthiamine, 5

The mechanism of formation of thiamine from 35S-chloroethylthiamine and the metabolic pathway as well as the main metabolites of the compound in chick were studied. Thiamine was found to be formed by tissue segments from the lower small intestine, while only a little by the liver slices. The formation was dependent of the incubation temperature and inhibited by sulfhydryl inhibitors such as p-chloromercuribenzoate, N-ethylmaleimide and monoiodoacetic acid or by heat-denaturation. On the other hand, sulfhydryl compounds such as glutathione and cysteine could not show any stimulating effect on thiamine formation. The feces and intestinal contents could not metabolize chloroethylthiamine to thiamine and Neomycin did not depress the thiamine formation by the intestine, indicating that intestinal flora does not play a role in the thiamine formation. These results suggest that thiamine may be produced by an enzymatic reaction sensitive to SH-inhibitor in the lower small intestine. However, the main metabolic pathway was shown to be a nonenzymatic formation of chloroethylthiamine to thiamine anhydride, followed by an enzymatic oxidation to its sulfoxide and sulfone presumably by P-450 dependent mixed function oxygenase of liver microsomes. Thiamine acetic acid was also identified as a minor metabolite of chloroethylthiamine.