Effect of thiouracil in modifying folate function in severe vitamin B 12 deficiency

Abstract

The effects of thiouracil in correcting defects in folic acid function produced by B 12 deficiency were studied. Addition of the thyroid inhibitor, thiouracil, to a low methionine diet containing B 12, increased the oxidation of [2- 14C]histidine to carbon dioxide, and increased liver folate levels. Addition of 10% pectin to the diet accentuated B 12 deficiency as evidenced by a greatly decreased rate of histidine oxidation (0.19%) and an increased excretion of methylmalonic acid. Addition of thiouracil to the diet restored folate function as measured by increased histidine oxidation and increased liver folate levels similar to that produced by addition of methionine to a B 12-deficient diet. Thiouracil decreased methylmalonate excretion, and increased hepatic levels of B 12 in animals on both B 12-deficient and -supplemented diets. Hepatic methionine synthase was increased by thiouracil, which may be the result of the elevated B 12 levels. S-Adenosylmethionine and the enzyme methionine adenosyltransferase were also increased by thiouracil. Thus it is possible that the effect of thiouracil in increasing folate function consists both in the effect of thiouracil in decreasing levels of methylenetetrahydrofolate reductase, and also in its action in increasing S-adenosylmethionine which exerts a feedback inhibition of this enzyme.