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KLEBANOFF
Myeloperoxidase: friend and foe.Klebanoff SJ. J Leukoc Biol. 2005 May;77(5):598-625. Epub 2005 Feb 2.
"Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes."
Iodination of arachidonic acid mediated by eosinophil peroxidase, myeloperoxidase and lactoperoxidase. Identification and comparison of products.Turk J, Henderson WR, Klebanoff SJ, Hubbard WC. Biochim Biophys Acta. 1983 Apr 13;751(2):189-200.
"Arachidonic acid undergoes iodination in the presence of hydrogen peroxide, iodide, and either eosinophil peroxidase, myeloperoxidase or lactoperoxidase. The profile of products generated by each of the three peroxidases is similar as determined by reversed-phase high-performance liquid chromatography. Structural analysis of the products indicate that: 1, each of the four double bonds in arachidonic acid is susceptible to iodination; 2, arachidonic acid can be multiply iodinated; and 3, the carboxylate moiety does not participate in the formation of all products. The isomeric composition of the isolated products indicates that peroxidase-mediated iodination of arachidonate is not stereoselective."
The iron-H2O2-iodide cytotoxic system.Klebanoff SJ J Exp Med. 1982 Oct 1;156(4):1262-7.
"A potent antimicrobial system is described which consists of ferrous sulfate (Fe2+), hydrogen peroxide (H2O2), and iodide in 0.02 M sodium acetate buffer pH 5.5. H2O2 could be replaced by the H2O2-generating system glucose + glucose oxidase. This system, unlike the myeloperoxidase-H2O2-halide system, was ineffective when iodide was replaced by bromide, chloride, or thyroxine, and was inhibited by EDTA, the hydroxyl radical scavengers mannitol and ethanol, and phosphate and lactate buffers at the same concentration and pH as the acetate buffer used. The acetate buffer, however, could be replaced by water. It is proposed that Fe2+ and H2O2 (Fenton's reagent) generate OH X (or a closely related substance), which interacts with iodide to form one or more toxic species."
Peroxidase-H2O2-halide system: Cytotoxic effect on mammalian tumor cells.Clark RA, Klebanoff SJ, Einstein AB, Fefer A. Blood. 1975 Feb;45(2):161-70. [abstract only]
"Myeloperoxidase, H2O2, and a halide constitute a potent antimicrobial system. A cytotoxic effect of this system on a line of mouse ascitic lymphoma cells (LSTRA) is demonstrated here using four different assay systems: 51Cr release, trypan blue exclusion, inhibition of glucose C-1 oxidation, and loss of oncogenicity for mice. Deletion of each component of the system, preheating the peroxidase, or addition of azide, cyanide, or catalase abolished the cytotoxicity. Myeloperoxidase was effective with either chloride or iodide as the halide, while lastoperoxidase was effective with iodide but not chloride. The iodinated thyroid hormones, triiodothyronine and thyroxine, could substitute for the halide, and H2O2 could be replaced by a peroxide-generating enzyme system such as glucose and glucose oxidase or by H2O2 producing bacteria such as pneumococci or streptococci. The possibility is raised that the peroxidases of inflammatory cells and certain biologic fluids may affect tumor initiation or growth in vivo."
Degradation of thyroid hormones by phagocytosing human leukocytes.Klebanoff SJ, Green WL. J Clin Invest. 1973 Jan;52(1):60-72.
"Thyroxine (T4) and triiodothyronine (T3) are rapidly degraded by a purified preparation of myeloperoxidase (MPO) and H2O2 with the formation of iodide and material which remains at the origin on paper chromatography. Deiodination by MPO and H2O2 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 H2O2 but inhibits this reaction when MPO is replaced by lactoperoxidase or horseradish peroxidase.
"Intact human leukocytes, in the resting state, degrade T4 and T3 slowly: degradation, however, is increased markedly during phagocytosis of preopsonized particles. Serum inhibits this reaction. T3 can be detected as a minor product of T4 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 H2O2 formation, degrade T4 and T3 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 T4 and T3 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 T4 and T3 by phagocytosing leukocytes. The role of leukocytic degradation of T4 and T3 in thyroid hormone economy and in leukocytic microbicidal activity is considered."
Myeloperoxidase-halide-hydrogen peroxide antibacterial system.Klebanoff SJ. J Bacteriol. 1968 Jun;95(6):2131-8.
"An antibacterial effect of myeloperoxidase, a halide, such as iodide, bromide, or chloride ion, and H202 on Escherichia coli or Lactobacillus acidophilus is described. When L. acidophilus was employed, the addition of H202 was not required; however, the protective effect of catalase suggested that, in this instance, H202 was generated by the organisms. The antibacterial effect was largely prevented by preheating the myeloperoxidase at 80 C or greater for 10 min or by the addition of a number of inhibitors; it was most active at the most acid pH employed (5.0). Lactoperoxidase was considerably less effective than was myeloperoxidase when chloride was the halide employed. Myeloperoxidase, at high concentrations, exerted an antibacterial effect on L. acidophilus in the absence of added halide, which also was temperature- and catalase-sensitive. Peroxidase was extracted from intact guinea pig leukocytes by weak acid, and the extract with peroxidase activity had antibacterial properties which were similar, in many respects, to those of the purified preparation of myeloperoxidase. Under appropriate conditions, the antibacterial effect was increased by halides and by H202 and was decreased by catalase, as well as by cyanide, azide, Tapazole, and thiosulfate. This suggests that, under the conditions employed, the antibacterial properties of a weak acid extract of guinea pig leukocytes is due, in part, to its peroxidase content, particularly if a halide is present in the reaction mixture. A heat-stable antibacterial agent or agents also appear to be present in the extract."
Iodination of bacteria: a bactericidal mechanism.Klebanoff SJ. J Exp Med. 1967 Dec 1;126(6):1063-78.
"Myeloperoxidase, iodide, and H2O2 have a bactericidal effect on Escherichia coli. Myeloperoxidase can be replaced in this system by lactoperoxidase or by a guinea pig leukocyte particulate preparation, H202 by an H202 generating system such as glucose and glucose oxidase, and iodide by thyroxine or triiodothyronine. The bactericidal effect was high at pH 5.0 and fell as the pH was increased.
"Preincubation of myeloperoxidase, iodide, and H202 for 30 min before the addition of the bacteria largely prevented the bactericidal effect. Thus, the organisms must be present in the reaction mixture during iodide oxidation for maximum killing, which suggests the involvement of labile intermediates of iodide oxidation rather than the more stable end products of oxidation such as iodine.
"Iodination of the bacteria by the myeloperoxidase-iodide-H2O2 system was demonstrated chemically and radioautographically. Iodination and the bactericidal effect were similarly affected by changes in experimental conditions in all the parameters tested (effect of preincubation, pH, and inhibitors).
"Phagocytosis of bacteria by guinea pig leukocytes was associated with the conversion of iodide to a trichloroacetic acid-precipitable form. Iodide was localized radioautographically in the cytoplasm of human leukocytes which contained ingested bacteria. Iodide fixation was not observed in the absence of phagocytosis or in the presence of Tapazole."
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