Inhibition of thyroid peroxidase by dietary flavonoids
Inhibition of thyroid peroxidase by dietary flavonoids
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DOI：
10.1021/tx950076m
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发表时间：
1996-01-01
影响因子：
4.1
通讯作者：
Doerge, DR
中科院分区：
文献类型：
--
作者：
Divi, RL;Doerge, DR
黄酮类化合物广泛存在于植物源性食品中，具有多种生物活性，包括在实验动物和人体中的抗甲状腺作用。对13种常用黄酮类化合物进行了结构-活性研究，以评估对甲状腺过氧化物酶（TPO）的抑制作用，TPO是催化甲状腺激素生物合成的酶。大多数黄酮类化合物测试TPO的有效抑制剂，与IC 50值范围从0.6到41 μ M。抑制更有效的化合物，非瑟酮，山奈酚，柚皮素，槲皮素，其中含有间苯二酚部分，是一致的TPO的失活机制为基础的，如先前观察到的间苯二酚和衍生物。其他黄酮类化合物通过不同的机制抑制TPO，如杨梅素和柚皮苷，表现出非竞争性抑制酪氨酸碘化相对于碘离子和线性混合型抑制相对于过氧化氢。相反，鹰嘴豆芽素A被发现是碘化的替代底物。主要产物6，8-二碘鹰嘴豆素A通过电喷雾质谱和H-1-NMR表征。黄酮类化合物的这些抑制机制与在实验动物中观察到的抗甲状腺作用一致，并且进一步预测了食用膳食黄酮类化合物的人类抗甲状腺作用的危害差异。在体内，自杀底物抑制，这只能通过从头蛋白质合成逆转，将是持久的。然而，可逆结合抑制剂和替代底物的作用将是暂时的，这是由于代谢和排泄的衰减。激素调节在甲状腺组织生长和增殖中的核心作用表明，类黄酮，特别是自杀底物的长期消耗，可能在甲状腺癌的病因学中发挥作用。
Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities including antithyroid effects in experimental animals and humans. A structure-activity study of 13 commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of TPO, with IC50 values ranging from 0.6 to 41 mu M. Inhibition by the more potent compounds, fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate substrate for iodination. The major product, 6,8-diiodo-biochanin A, was characterized by electrospray mass spectrometry and H-1-NMR. These inhibitory mechanisms for flavonoids are consistent with the antithyroid effects observed in experimental animals and, further, predict differences in hazards for antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of reversible binding inhibitors and alternate substrates would be temporary due to attenuation by metabolism and excretion. The central role of hormonal regulation in growth and proliferation of thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could play a role in the etiology of thyroid cancer.