methimazole and Phagocyte-Bactericidal-Dysfunction

Thyroxine (T(4)) and triiodothyronine (T(9)) are rapidly degraded by a purified preparation of myeloperoxidase (MPO) and H(2)O(2) with the formation of iodide and material which remains at the origin on paper chromatography. Deiodination by MPO and H(2)O(2) occurs more readily at pH 7.0 than at pH 5.0 in contrast to iodination by this system which is known to occur more readily at pH 5.0 than at pH 7.0. Degradation is inhibited by azide, cyanide, ascorbic acid, and propylthiouracil. Methimazole stimulates deiodination by MPO and H(2)O(2) but inhibits this reaction when MPO is replaced by lactoperoxidase or horseradish peroxidase.Intact human leukocytes, in the resting state, degrade T(4) and T(3) slowly: degradation, however, is increased markedly during phagocytosis of preopsonized particles. Serum inhibits this reaction. T(3) can be detected as a minor product of T(4) degradation. Proteolytic digestion of the reaction products increases the recovery of monoiodotyrosine. The fixation of iodine in the cytoplasm of leukocytes which contain ingested bacteria was detected radioautographically. Chronic granulomatous disease leukocytes, which are deficient in H(2)O(2) formation, degrade T(4) and T(3) poorly during phagocytosis. MPO-deficient leukocytes degrade the thyroid hormones at a slower rate than do normal leukocytes although considerable degradation is still observed. Azide, cyanide, ascorbic acid, and propylthiouracil which inhibit certain peroxidasecatalyzed reactions inhibit degradation by normal leukocytes; however, inhibition is incomplete. Formation of iodinated origin material is inhibited to a greater degree by azide, cyanide, and propylthiouracil than is deiodination. Methimazole inhibits the formation of iodinated origin material by both normal and MPO-deficient leukocytes. However, deiodination by normal leukocytes is stimulated and that of MPO-deficient leukocytes is unaffected by methimazole. Hypoxia inhibits the degradation of T(4) and T(3) by untreated normal or MPO-deficient leukocytes and by normal leukocytes treated with azide or methimazole. These data suggest that both MPO-dependent and MPO-independent systems are involved in the degradation of T(4) and T(3) by phagocytosing leukocytes. The role of leukocytic degradation of T(4) and T(3) in thyroid hormone economy and in leukocytic microbicidal activity is considered.

Topics: Ascorbic Acid; Azides; Chromatography, Gel; Chromatography, Paper; Cyanides; Electrophoresis, Paper; Humans; Hydrogen Peroxide; In Vitro Techniques; Iodine Isotopes; Lactobacillus acidophilus; Leukocytes; Metabolism, Inborn Errors; Methimazole; Oxygen; Peroxidases; Phagocyte Bactericidal Dysfunction; Phagocytosis; Propylthiouracil; Thyroid Hormones; Thyroxine; Triiodothyronine

Topics: Azides; Botulinum Toxins; Calcium Isotopes; Clostridium botulinum; Colchicine; Glyceraldehyde; Glycolysis; Humans; Hydrocortisone; Hydrogen Peroxide; Hydrogen-Ion Concentration; In Vitro Techniques; Iodine; Leukocytes; Lysosomes; Male; Methimazole; Neutrophils; Peroxidases; Phagocyte Bactericidal Dysfunction; Phagocytosis; Spores; Spores, Bacterial