Gupta A, Eggo M C, Uetrecht J P, Cribb A E, Daneman D, Rieder M J, Shear N H, Cannon M, Spielberg S P
Faculty of Medicine, Department of Paediatrics, University of Toronto.
Clin Pharmacol Ther. 1992 Jan;51(1):56-67. doi: 10.1038/clpt.1992.8.
Inherited defects in detoxification of reactive metabolites of drugs predispose patients to "hypersensitivity" reactions. Covalent interaction of metabolites with cell macromolecules leads to cytotoxic and immunologic outcomes, manifested clinically by multisystem syndromes with variable organ involvement. Hypothyroidism developed in 5 of 202 patients (age range, 1 to 81 years) we investigated for hypersensitivity reactions to anticonvulsants or sulfonamides shortly after their reaction. None had previous personal or family histories of autoimmune disease. All had low thyroxine levels, elevated levels of thyroid stimulating hormone, and autoantibodies including antimicrosomal antibodies. Patients were 2 to 18 years of age at presentation, and two were male. All returned to a euthyroid state within a year of presentation, and all remain well. The demographics, clinical presentation, and course of the patients is atypical of idiopathic lymphocytic thyroiditis. We investigated the pathogenesis of thyroid toxicity using the hydroxylamine metabolite of sulfamethoxazole as a model. The hydroxyalmine was toxic to thyroid cells in vitro, which did or did not express thyroid peroxidase activity, whereas the parent sulfonamide was toxic only to cells with active thyroid peroxidase. The purified enzyme converted sulfamethoxazole to the hydroxylamine. Formation of reactive drug metabolites by thyroid peroxidase in a host who is genetically unable to detoxify the metabolites may lead directly to cytotoxicity. Covalent binding to macromolecules, including thyroid peroxidase, also may lead to expression of neoantigens and formation of autoantibodies. Patients who have sustained hypersensitivity reactions to drugs should be investigated for possible involvement of the thyroid.
药物反应性代谢产物解毒的遗传性缺陷使患者易发生“过敏”反应。代谢产物与细胞大分子的共价相互作用导致细胞毒性和免疫反应，临床上表现为多系统综合征，累及不同器官。在我们调查的202例对抗惊厥药或磺胺类药物过敏反应的患者（年龄范围为1至81岁）中，有5例在反应后不久出现甲状腺功能减退。他们既往均无自身免疫性疾病的个人史或家族史。所有患者甲状腺素水平低，促甲状腺激素水平升高，且存在自身抗体，包括抗微粒体抗体。患者就诊时年龄为2至18岁，其中2例为男性。所有患者在就诊后一年内恢复到甲状腺功能正常状态，且目前情况良好。这些患者的人口统计学特征、临床表现及病程不符合特发性淋巴细胞性甲状腺炎的典型表现。我们以磺胺甲恶唑的羟胺代谢产物为模型研究了甲状腺毒性的发病机制。羟胺在体外对有或无甲状腺过氧化物酶活性的甲状腺细胞均有毒性，而母体磺胺仅对有活性甲状腺过氧化物酶的细胞有毒性。纯化的酶可将磺胺甲恶唑转化为羟胺。甲状腺过氧化物酶在遗传上无法对代谢产物进行解毒的宿主中形成反应性药物代谢产物可能直接导致细胞毒性。与包括甲状腺过氧化物酶在内之大分的共价结合也可能导致新抗原的表达和自身抗体的形成。对药物持续发生过敏反应的患者应检查甲状腺是否可能受累。
