OLFACTORY TOXICITY OF METHIMAZOLE - DOSE-RESPONSE AND STRUCTURE-ACTIVITY STUDIES AND CHARACTERIZATION OF FLAVIN-CONTAINING MONOOXYGENASE ACTIVITY IN THE LONG-EVANS RAT OLFACTORY MUCOSA
OLFACTORY TOXICITY OF METHIMAZOLE - DOSE-RESPONSE AND STRUCTURE-ACTIVITY STUDIES AND CHARACTERIZATION OF FLAVIN-CONTAINING MONOOXYGENASE ACTIVITY IN THE LONG-EVANS RAT OLFACTORY MUCOSA
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DOI：
10.1177/019262339502300404
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发表时间：
1995-07-01
影响因子：
1.5
通讯作者：
LEVI, PE
中科院分区：
文献类型：
--
作者：
GENTER, MB;DEAMER, NJ;LEVI, PE
甲巯咪唑是一种用于人类治疗甲状腺功能亢进症的化合物，在实验中用作含黄素单加氧酶（FMO）系统的模型底物。该实验室的先前结果表明，甲巯咪唑是一种嗅觉系统毒物，单次ip给药300 mg/kg后，导致雄性Long-Evans大鼠的嗅觉上皮几乎完全破坏。本研究旨在确定甲巯咪唑诱导的嗅觉粘膜损伤的剂量-反应关系，并确定口服给药是否会发生类似的损伤，模拟人体暴露的相关途径。我们还通过结构-活性研究研究了甲巯咪唑的嗅觉毒性机制，并开始表征雄性Long-Evans大鼠嗅觉粘膜中存在的FMO形式。剂量-反应分析表明，甲巯咪唑在25 mg/kg ip或更高剂量下引起嗅觉粘膜损伤。灌胃研究的结果表明，50 mg/kg的单次口服剂量也会引起嗅觉粘膜损伤。两个结构相关的化合物，甲基咪唑和甲基吡咯，不是嗅觉毒物，这表明在代谢甲巯咪唑的过程中产生的反应中间体的S-氧化物是嗅觉有毒物质。微粒体孵育研究显示，在嗅觉粘膜微粒体中存在与肝脏中水平相当的甲巯咪唑S-氧化活性。抗小鼠肝FMO抗体与嗅觉粘膜微粒体的Western印迹反应。这些研究结果表明，甲巯咪唑的嗅觉毒性的剂量反应，并表明，表征人类嗅觉粘膜FMO活性可能是必要的，以评估潜在的人类风险与治疗暴露于甲巯咪唑。
Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for the flavin-containing monooxygenase (FMO) system. Previous results from this laboratory demonstrated that methimazole is an olfactory system toxicant, causing nearly complete destruction of the olfactory epithelium in the male Long-Evans rat following a single ip dose of 300 mg/kg. The present studies were undertaken to determine the dose-response relationship for methimazole-induced olfactory mucosal damage and to determine whether or not similar damage occurs as a result of oral administration, mimicking the relevant route of human exposure. We also investigated the mechanism of olfactory toxicity of methimazole by means of a structure-activity study and began the characterization of the form(s) of FMO present in the olfactory mucosa of the male Long-Evans rat. Dose-response analysis demonstrated that methimazole causes olfactory mucosal damage at doses of 25 mg/kg ip and greater. The results of gavage studies showed that a single oral dose of 50 mg/kg also caused olfactory mucosal damage. Two structurally related compounds, methylimidazole and methylpyrrole, were not olfactory toxicants, suggesting that a reactive intermediate generated in the course of metabolizing methimazole to an S-oxide is the olfactory toxic species. Microsomal incubation studies revealed the presence of methimazole S-oxidation activity in olfactory mucosal microsomes at levels comparable to those in liver. An anti-mouse liver FMO antibody reacted on Western blots with olfactory mucosal microsomes. These findings demonstrate a dose-response for the olfactory toxicity of methimazole and suggest that characterization of human olfactory mucosal FMO activity may be necessary to assess the potential for human risk associated with therapeutic exposure to methimazole.