The Influence of Methimazole and Its Putative Metabolites on Human Polymorphonuclear Leukocyte Function

McGroarty, Jacqueline A (1986) The Influence of Methimazole and Its Putative Metabolites on Human Polymorphonuclear Leukocyte Function. PhD thesis, University of Glasgow.

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An uncommon side effect of treatment with antithyroid drugs is agranulocytosis. These compounds are also known to be capable of modifying immune function in humans. The polymorphonuclear leukocytes are responsible for clearing invading foreign bodies from the bloodstream, and as such are the first line of defence against infection. The effect of methimazole, a thioureylene antithyroid drug commonly used in the treatment of hyperthyroidism, on selected parameters of polymorphonuclear leukocyte function, was investigated. Methimazole is metabolised by polymorphonuclear leukocytes, therefore the influence of some of its putative metabolites, namely 3-methylthiohydantoin, methylhydantoin and N-methylimidazole, was also assessed. The chemotactic, phagocytic and cidal capabilities of human polymorphonuclear leukocytes were examined. The ability of polymorphonuclear leukocytes to migrate under agarose towards the chemo-attractant, zymosan-stimulated serum, was found to be unaffected by methimazole, 3-methylthiohydantoin, methylhydantoin and methylimidazole at concentrations between 10-3 and 10-7 M. Phagocytosis of S, aureus, S. pyogenes, E. coli, L. casei and C. albicans proceded normally in the presence of 10-3 M methimazole, S. pyogenes and S. aureus, as representatives of hydrogen peroxide- and non-hydrogen peroxide producing bacteria respectively were the subject of further investigation which established that methimazole, 3-methylthiohydantoin, methylhydantoin and N- methyliraidazole did not significantly affect their ingestion at concentrations between 10-3 and 10-5M. Intracellular killing of all five pre-opsonised microorganisms by human polymorphonuclear leukocytes treated with 10-3M methimazole was stimulated by between ten and 40 per cent after 30 minutes co-incubation. Between 60 and 120 minutes there was no evidence of any significant stimulation. Further investigation with S. pyogenes and S. aureus revealed that methimazole, 3-methylthiohydantoin, methylhydantoin and N-methylimidazole exerted no significant effect on the killing of S. pyogenes, however dose-related inhibition was evident on treatment with between 10 and 10-5M methimazole and 3-methylthiohydantoin during phagocytosis of S. aureus. Methylhydantoin and N-methyl-imidazole produced no significant effects. The oxygen consumption of latex-stimulated polymorphonuclear leukocytes was found to be stimulated by 48 and 58 per cent respectively by methimazole and N-methylimidazole at 10 M, 3-methylthiohydantoin and methylhydantoin producing no significant change. The hexose monophosphate shunt activity of similarly stimulated polymorphonuclear leukocytes significantly increased by up to 20 per cent in the presence of methimazole, 3-methylthiohydantoin and N-methylinidazole. None of the compounds exerted any influence on the release of lysosomal enzymes by stimulated polymorphonuclear leukocytes, however methimazole, 3-methylthiohydantoin and N-methylimidazole inhibited myeloperoxidase activity by between 36 and 100 per cent at 10 14, this inhibition was dose-related at concentrations between 10-3 and 10-5M. Lysozyme and lactoferrin activity from the released lysosomal enzymes was unaffected by any of the four compounds, neither was the lysozyme activity of intact polymorphonuclear leukocytes. Alkaline phosphatase activity however was inhibited by around 50 per cent by methimazole and 3-methyl- thiohydantoin at concentrations of 10-3 M; again the inhibitory effect was significantly dose-related. Thus it would appear that methimazole acts, not by inhibiting the microbicidal oxidase system, as might have been expected, but by altering myeloperoxidase activity. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Pharmacology, Immunology
Date of Award: 1986
Depositing User: Enlighten Team
Unique ID: glathesis:1986-77381
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:10
Last Modified: 14 Jan 2020 09:10

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