Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions. 217 25

Ultrastructural localization and intensity of endogenous thyroid peroxidase (TPO) in Hashimoto's thyroiditis were examined in relation to the serum thyroid hormone level, thyroid-stimulating hormone (TSH) concentration and anti-thyroid autoantibody titer. In Hashimoto's thyroiditis, TPO activity on the microvilli of follicular cells was more intense than that of normal thyroid tissue, but the intensity of the intracytoplasmic peroxidase reaction was generally weaker than that of Graves' or normal thyroid tissue. Microvillar TPO reaction products were positive in all thyroid follicular cells in patients with increased TSH levels, but no TPO activity was observed on the microvilli of patients with normal or low TSH levels, irrespective of their histological type or serum anti-microsomal antibody titer. It is suggested that TPO activity on the surface of microvilli of thyroid follicular cells in Hashimoto's thyroid gland is modulated by thyrotropin but is not affected by anti-thyroid autoantibodies.
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PMID:Ultrastructural localization of endogenous peroxidase activity in Hashimoto's thyroiditis. 233 Aug 43

We developed a histochemical method to demonstrate iodide peroxidase activity in various thyroid disorders and compared it with the biochemical and ultrastructural-cytochemical methods. All of the 26 adenomatous goiters and 43 follicular adenomas were peroxidase-positive. In the 74 cases of thyroid carcinomas examined, about half of the follicular carcinomas (17 of 33 patients), and a few papillary carcinomas (3 of 41 patients) were peroxidase-positive. Peroxidase-negative cases were seen in 70% (52 of 74 patients) of the follicular and papillary carcinomas. All the non-tumorous thyroid tissues adjacent to various disorders were peroxidase-positive. Since our histochemically demonstrated peroxidase activities almost parallel those determined biochemically and ultrastructural-cytochemically, we conclude that histochemical examination is a simple and useful method for the detection of peroxidase activity. As for the relationships between histochemically proved peroxidase activity and the histology of tumors, the histological differentiation of tumors was not consistent with their functional differentiation classified according to peroxidase activity.
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PMID:Histochemical determination of iodide peroxidase activity in various thyroid disorders. 239 55

Pools of sera from patients with Graves' disease or Hashimoto's thyroiditis highly inhibit the binding to human thyroid membranes of one of 19 monoclonal antibodies raised against preparations of human thyroid membranes. This monoclonal antibody reacts with human and bovine thyroid peroxidase and bovine lactoperoxidase but not with human hemoglobin, cytochrome c and other related molecules. These results indicate that the thyroid peroxidase and the microsomal antigen are antigenically related. These data taken together with those from other groups, highly suggest that thyroid peroxidase is the microsomal antigen involved in autoimmune thyroid diseases.
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PMID:[Antigenic relation between thyroid peroxidase and the microsomal antigen implicated in auto-immune diseases of the thyroid]. 241 85

We have characterized thyroid microsomal antigen (M-Ag) prepared from Graves' and normal thyroid tissues using 100,000 x g thyroid membrane fractions in enzyme-linked immunosorbent assays with pooled polyclonal human sera containing high titers of antibody to M-Ag. A ten-fold parallel increase in dose inhibition potencies occurred with M-Ag preparations from Graves' as compared to normal thyroid tissue. The M-Ag preparations were further evaluated by SDS-polyacrylamide gel electrophoresis and proteins visualized by Western blot using high titer microsomal antibody (M-Ab) sera (n = 2) devoid of thyroglobulin antibody activity. We found discrete 100 kD relative molecular mass bands in Graves' M-Ag preparations (n = 3) under nonreducing conditions which were only poorly resolved in normal thyroid M-Ag (n = 3) using up to 100 micrograms of protein per lane. The cellular localization of M-Ag was then investigated using the avidin-biotin-peroxidase technique on frozen sections of Graves' and normal human thyroid tissue with a murine monoclonal antibody reactive with human M-Ag and thyroid peroxidase. M-Ag reactivity was similar in both Graves' and normal thyroid tissues and localized to the entire follicular cell membrane with more intense staining occurring on the inner follicular cell membrane. This was in contrast to follicular cell staining for HLA-DR antigen which was present in 6 of 10 Graves' tissues examined and absent in normal thyroid tissue. Staining for HLA-DR antigen also occurred on the follicular cell surface membrane with occasional enhancement at the thyrocyte apical cell membrane. We conclude: a) M-Ag is induced approximately 10-fold in Graves' thyroid tissue and can be objectively quantified in ELISA systems, 2) There were no detectable qualitative differences between M-Ag from Graves' and normal thyroid tissue, and 3) HLA-DR antigen was detected on 60% Graves' tissues in a cell surface distribution similar to that observed for M-Ag in both Graves' and normal tissues.
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PMID:Induction of microsomal antigen and comparison with histologic localization of HLA-DR in Graves' thyroid tissue. 249 9

We studied the distribution of binding sites for anti-peroxidase monoclonal antibody and anti-microsomal antibodies on isolated human thyroid follicles and a human thyroid cell line. Both open follicles and cells were incubated first with antibodies at +4 degrees C, then with colloidal gold labelled protein A. The topography of the binding sites for monoclonal anti-peroxidase antibody corresponded closely to the expected cell surface distribution of endogenous thyroid peroxidase since labelling was observed at the apical cell surface of the follicles. Furthermore, labelling was restricted to the microvilli level; while smooth membrane territories were devoid of binding sites. In some cases, incubations at 4 degrees C were followed by warming the follicles and cells up to 37 degrees C for 20 minutes in order to study internalization of ligands. Ligands were then observed in intracellular organelles: endosomes and lysosomes. Essentially the same results were observed when human antibodies to the microsomal antigen were used. Controls with microsomal antibodies depleted in anti-peroxidase were negative. In conclusion these findings show that: 1) thyroid peroxidase is present in limited areas on the apical cell surface, 2) labelling of follicles and cells by the anti-microsomal antibodies had the same pattern of distribution as the monoclonal anti-peroxidase antibody, thus suggesting that they recognize the same apical antigens, and 3) TPO/MIC antigen traffics from the cell surface towards lysosomes when the cells are incubated at 37 degrees C.
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PMID:Immunocytochemical study of localization and traffic of thyroid peroxidase/microsomal antigen. 249 23

This study describes an assay for the detection of cytotoxicity for thyroid cells in serum of patients with autoimmune thyroiditis. Quantitative measurement may be performed by DNA or [3H] leucine incorporation determinations. The cytotoxic effect is localized in the gamma-globulin fraction, and is complement-mediated. It is thyroid specific i.e. it is not observed with fibroblasts and patients with other autoimmune diseases (patients with lupus erythematosis or glomerulonephritis) do not have cytotoxic antibodies directed against thyroid cells. The thyroid cytotoxicity is related to the presence of antimicrosomal antibodies and the effect of circulating antibodies is inhibited by human thyroid peroxidase. These results strengthen the possible implication of circulating antithyroid peroxidase antibodies in thyroid damage observed in autoimmune thyroiditis.
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PMID:Cytotoxic assay of circulating thyroid peroxidase antibodies. 249 49

Peroxidase activities of autonomously functioning thyroid tumors (T) and surrounding non-tumorous tissue (N) in 5 patients were determined by employing guaiacol or iodide as the second substrates. The mean values for specific activities of T were 30 times (in iodide oxidation assay) or 4 times (in guaiacol oxidation assay) as high as those in N, being significantly higher than those of non-functioning tumors. The thyroglobulin-iodination activity of thyroid peroxidase in T was also found to correlate well to the iodide oxidation activity. These results suggest that the enhanced peroxidase activity in the nodules plays an essential role in the function of autonomously functioning thyroid nodules.
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PMID:Peroxidase activities in autonomously functioning nodules and adjacent non-tumorous portions of thyroids. 251 57

Amitrole (3-amino-1,2,4-triazole) meets the criteria for a suicide (mechanism-based) inhibitor of lactoperoxidase. Amitrole causes rapid inactivation of lactoperoxidase only in the presence of hydrogen peroxide, and the kinetics are consistent with a suicide mechanism. Approximately 7 mol of radiolabeled amitrole binds covalently per equivalent of lactoperoxidase activity lost. The visible spectrum of lactoperoxidase inactivated by amitrole is unchanged, suggesting that covalent modification of the heme prosthetic group does not occur. The 13C NMR spectrum of lactoperoxidase inactivated by [13C]amitrole shows unique resonances which support the hypothesis that covalent binding occurs on the protein moiety. The similarities between lactoperoxidase and thyroid peroxidase suggest a similar mechanism for inhibition of thyroid hormone synthesis by amitrole.
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PMID:Suicide inactivation of lactoperoxidase by 3-amino-1,2,4-triazole. 251 7

The plasma membrane fraction from porcine thyroid is known to exhibit an NADPH-dependent production of hydrogen peroxide (H2O2), which is utilized for the oxidative biosynthesis of thyroid hormones catalyzed by thyroid peroxidase. The H2O2 formation is cyanide-insensitive, ATP-activatable, and Ca2+-dependent (Nakamura, Y., Ogihara, S., and Ohtaki, S. (1987) J. Biochem. (Tokyo) 102, 1121-1132). It remains unknown, however, whether H2O2 is produced directly from molecular oxygen (O2) or formed via dismutation of superoxide anion (O2-). We therefore attempted to analyze the mechanism of H2O2 formation by utilizing a new method for the simultaneous measurement of O2- and H2O2, in which diacetyldeuteroheme-substituted horseradish peroxidase was employed as the trapping agent for both oxygen metabolites. When NADPH was incubated with the membrane fraction in the presence of the heme-substituted peroxidase, a massive O2 consumption was observed together with the formation of compound III, and O2- adduct of the peroxidase. The amounts of compound III formed and O2 consumed were stoichiometric with each other, while formation of compound II, an indicative of H2O2, was not observed during the reaction. On the other hand, when an excess amount of superoxide dismutase was included in the reaction mixture, compound II was produced with complete suppression of the compound III formation. NADH minimally supported both O2 consumption and formation of compound III or II. These results indicate that the NADPH oxidase in the plasma membrane of thyroid produces O2- as the primary metabolite of O2 and hence that H2O2 required for the thyroid hormone synthesis provided through the dismutation of O2-.
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PMID:Superoxide anion is the initial product in the hydrogen peroxide formation catalyzed by NADPH oxidase in porcine thyroid plasma membrane. 253 59


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