thiouracil and Vitamin-B-12-Deficiency

The effects of thiouracil in correcting defects in folic acid function produced by B12 deficiency were studied. Addition of the thyroid inhibitor, thiouracil, to a low methionine diet containing B12, increased the oxidation of [2-14C]histidine to carbon dioxide, and increased liver folate levels. Addition of 10% pectin to the diet accentuated B12 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 B12-deficient diet. Thiouracil decreased methylmalonate excretion, and increased hepatic levels of B12 in animals on both B12-deficient and -supplemented diets. Hepatic methionine synthase was increased by thiouracil, which may be the result of the elevated B12 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.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Carbon Dioxide; Diet; Folic Acid; Histidine; Liver; Male; Methylmalonic Acid; Oxidation-Reduction; Pectins; Rats; Rats, Inbred Strains; Thiouracil; Vitamin B 12; Vitamin B 12 Deficiency

The effect of hypo- and hyperthyroidism on vitamin B-12 metabolism in the rat was studied by measuring methylmalonic acid excretion, B-12 content of liver and oxidation of 2-[14C]histidine. Ten percent pectin was added to increase severity of B-12 deficiency. The addition of thiouracil to a diet containing 10% pectin decreased the excretion of methylmalonic acid suggesting an amelioration of the B-12 deficiency. It was found that part of this decreased methylmalonic acid excretion was due to a decreased food consumption with a correspondingly decreased intake of branched-chain amino acids which are precursors of methylmalonic acid. When attempts were made to increase the protein intake of animals receiving thiouracil so their amino acid intake was equal to that of the control animals, methylmalonic acid excretion was still lower than that of the controls. It was also found that the vitamin B-12 content of the liver was higher in the animals receiving thiouracil than in the controls. Thyroidectomy had the same effect as feeding thiouracil. Liver B-12 levels are rapidly depleted on a B-12 deficient diet containing 10% pectin. It appears that hypothyroidism, induced either by thyroidectomy or by feeding thiouracil, slows the rate of depletion of hepatic B-12 which in turn facilitates the metabolism of methylmalonic acid and decreases its excretion in the urine.

Topics: Animals; Dietary Proteins; Folic Acid; Histidine; Hypothyroidism; Liver; Malonates; Methylmalonic Acid; Mice; Rats; Thiouracil; Thyroid Hormones; Thyroidectomy; Vitamin B 12; Vitamin B 12 Deficiency