他巴唑抑制甲状腺激素合成的机理

对他巴唑影响甲状腺过氧化物酶（TPO）催化的四甲基联苯胺（TMB）显色反应及酪氨酸碘化反应进行了研究。结果表明，他巴唑不抑制TPO，主要是通过夺去反应中必需的活性氧影响TMB的显色及酪氨酸的碘化。     

抗甲状腺药体外抑制前列腺素合成的作用

在前列腺素的生物合成过程中,花生四烯酸在过氧化物酶作用下转变为前列腺素内过氧化物是一个重要的步骤。已经证明抗甲状腺药甲硫咪唑(Methimazo-le,他巴唑)、甲亢平(Carbimazole)等能抑制甲状腺细胞内的过氧化物酶,使离子碘不能氧化为活性碘,阻止酪氨酸碘化和碘化酪氨酸的偶联,从而干扰甲状腺素的合成。但抗甲状腺药并非特异性抑制甲状腺细胞内的     

甲巯咪唑片致药疹2例

甲巯咪唑（Thiamazol）,又名他巴唑（Methirnazol）,是一种咪唑类抗甲状腺药,主要用于治疗甲状腺功能亢进症,其作用机制是通过抑制甲状腺内过氧化物酶,阻止摄入到甲状腺内的碘化物氧化及酪氨酸的偶联,从而阻碍甲状腺素（T4）和三碘甲状腺氨酸（T3）的合成。其主要不良反应为白细胞减少症、恶心、呕吐、口中有苦味等,过敏性反应报道较少见。例1,男,28岁,诊断：“突眼性甲状腺肿（Graves’病）”。给予他巴唑（上海黄海制药厂,批号96090350）且日30mg以抑制甲状腺素合成,治疗10d后出现全身搔痒,眼睑浮肿、咽喉部异物感,并出现…     

钙通道阻滞剂抗肝缺血—再灌注损伤作用机制的实验研究

目的 探讨钙通道阻滞剂（ＣＣＥＢ）对肝缺血一再灌注损伤（ＨＩＲＩ）防治作用的机制。方法制备家兔ＨＩＲＩ模型,动态观察维拉帕米（ＶＰ）和地尔硫卓（ＤＴ）对肝组织及血中黄嘌呤氧化酶（ＸＯ）、超氧化物歧化酶（ＳＯＤ）活性及脂质过氧化物（ＬＰＯ）浓度的影响。结果 ＶＰ组和ＤＴ组ＯＸ活性及ＭＤＡ含量分别显著低于对照组（均Ｐ＜０．０１）,而ＳＯＤ活性与对照组比较均无显著性差异（均 Ｐ＞ ０．０５）。结论 ＣＣＥＢ抗 ＨＩＲＩ的机制与其降低 ＸＯ活性、抑制脂质过氧化反应密切相关。     

甲状腺过氧化物酶抗体的临床应用

甲状腺疾病是一组比较复杂的内分泌疾病,用于该疾病检测的实验室项目也日益增多,今天我们主要讨论甲状腺过氧化物酶抗体在我院临床诊断甲状腺类疾病的应用。甲状腺过氧化物酶（TPO）是位于甲状腺上皮细胞的顶端细胞膜上,直接参与甲状腺细胞中的氧化酪氨酸的碘化及碘化酪氨酸的偶联等。它是甲状腺激素合成过程中的关键酶。TPO 也是自身免疫性甲状腺疾病的(AITD)一种重要的自身抗原,可以刺激机体免疫系统产生TPO抗体（TPO-Ab）。TPO-Ab作为AITD一种主要的自身抗体,可通过激活补体,抗体依赖细胞介导的细胞毒作用和致敏的T杀伤细胞直接杀伤等作用机制,引起甲状腺滤胞损伤,间接的抑制甲状腺的合成,导致甲状腺功能减退的主要机制。所以TPO-Ab水平的检测是诊断AITD的一项不可缺少的实验室指标。     

Mechanisms of Inhibitory Effects of Breviscapine on Lipid Peroxidation in Rat Brain Mitochondria

本文研究了灯盏花素抑制脂质过氧化的作用机制。大鼠脑线粒体脂质过氧化物用硫代巴比妥酸比色法测定。灯盏花素与铁的螯合活性用差示光谱法测定。黄嘌呤黄嘌呤氧化酶（ＸａｎＸＯ）体系产生的超氧阴离子自由基（Ｏ２）及ＦｅＳＯ４Ｈ２Ｏ２体系产生的羟自由基（·ＯＨ）用比色法测定。结果表明：灯盏花素能有效地抑制ＸａｎＸＯ和ＦｅＳＯ４Ｈ２Ｏ２诱导的脑线粒体脂质过氧化反应，其ＩＣ５０分别为９３０１和６２１８μｍｏｌ·Ｌ－１。灯盏花素也能清除ＸａｎＸＯ体系产生的Ｏ２和ＦｅＳＯ４Ｈ２Ｏ２体系产生的·ＯＨ，其ＩＣ５０分别为３２６３和２０２２μｍｏｌ·Ｌ－１。灯盏花素还具有螯合Ｆｅ２＋的活性。由此可见，灯盏花素是在氧自由基与线粒体膜的反应中（１）·ＯＨ的形成（通过与Ｆｅ２＋螯合）（２）脂质过氧化的启动（通过清除Ｏ２和·ＯＨ）两个环节抑制脂质过氧化反应的。清除氧自由基和与Ｆｅ２＋螯合是灯盏花素抑制脑线粒体脂质过氧化的作用机制     

甲巯咪唑的不良反应及其合理应用

甲巯咪唑(他巴唑)为甲亢治疗药。其作用机制为抑制甲状腺过氧化物酶,阻止碘离子氧化,酪氨酸磺化,以及碘化酪氨酸的偶联,从而抑制甲状腺激素的生物合成,但不能对抗甲状腺激素的作用,也不能阻止已合成甲状腺激素的释放。其治疗作用是在已合成的甲状腺素耗竭后3～4周或以上时出现。本品尚有一定的兔疫抑制作用。本品口服后由胃肠道吸收迅速完全,半衰期3～6h,甲巯咪唑及代谢产物约65％～80％于48h内经尿排出。 本品用于治疗Gravse病,甲状腺腺瘤,结节性甲状腺肿及甲状腺癌所引起的各种类型的甲状腺功能亢进症。1 国内不良反应文献检索情况 检索了甲巯咪唑不良反应中文文献133篇(1964～2001年)不良反应共462例,其中死亡9例,见表1。     

氧化白藜芦醇对酪氨酸酶的抑制作用

目的研究氧化白藜芦醇对酪氨酸酶抑制的作用机制。方法将N-乙酰-L-酪氨酸代替酪氨酸作为底物,HPLC动态监测氧化白藜芦醇对酶催化生成多巴醌的影响;将对苯醌代替多巴醌,HPLC动态监测其对非酶催化生成多巴色素的影响;分别以左旋酪氨酸和左旋多巴为底物,在pH 6.8的磷酸盐缓冲体系反应后测定475 nm吸光度值,研究氧化白藜芦醇对酪氨酸酶催化反应进程和酶活性抑制的影响,计算酶的抑制动力学参数。结果氧化白藜芦醇对酪氨酸酶催化过程有抑制作用,对非酶催化过程有促进作用。对酪氨酸酶单酚酶、二酚酶均有抑制作用,半抑制浓度(IC50)分别为2.48μmol/L、0.020 mmol/L。结论氧化白藜芦醇对酪氨酸酶的抑制类型为可逆抑制中的非竞争性抑制。     

大肠杆菌过氧化DNA损伤及红景天酪醇对其抑制作用

本实验测定酪醇对经过氧化氢（Ｈ２Ｏ２）共处理和后处理后的大肠杆菌ＰＱ６６及其ｏｘｙＲ基因缺失突变体ＯＧ４００的过氧化损伤的抑制作用，并比较了二甲亚砜（ＤＭＳＯ）的作用。结果显示，酪醇对ＰＱ６６和ＯＧ４００的过氧化损伤都有抑制作用，而且对ＯＧ４００的抑制作用明显高于ＰＱ６６。这说明酪醇的抑制作用与ｏｘｙＲ基因有关，但不存在必然的联系。此外酪醇在细菌细胞内外都有抑制作用。在细胞外抑制效果约为２６００倍浓度的ＤＭＳＯ。     

茶多酚清除氧自由基及抑制脑脂质过氧化反应的体外试验

目的研究茶多酚对羟自由基（·ＯＨ）、超氧阴离子自由基（Ｏ·２）的清除作用及其对脂质过氧化的抑制作用。方法茶多酚与自由基发生体系或大鼠脑线粒体共浴后，比色法测定·ＯＨ、Ｏ·２及丙二醛生成量。结果茶多酚对Ｆｅｎｔｏｎ反应生成的·ＯＨ及黄嘌呤－黄嘌呤氧化酶系统产生的Ｏ·２具有较强的清除作用，ＩＣ５０分别为９１９．６ｍｇ·Ｌ－１和８３６ｍｇ·Ｌ－１。茶多酚对·ＯＨ诱导的离体大鼠脑线粒体产生的脂质过氧化有明显的抑制作用。结论茶多酚的抗脂质过氧化作用与其清除氧自由基作用有关     

Inhibition of peroxidase activity by some non-steroidal anti-inflammatory drugs.

The non-steroidal anti-inflammatory drugs, indomethacin, flufenamic acid and naproxen inhibited thyroid peroxidase-catalyzed iodination of BSA in vitro. Inhibition by all three drugs was affected more effectively in a hydrogen peroxide generating system than in an incubation system in which hydrogen peroxide was added. Naproxen differed from the other two drugs in so far as it inhibited mainly hydrogen peroxide generation while its comparatively low inhibitory influence (>20%) on TPO was not dose-dependent. The inhibitory influence of these anti-inflammatory drugs was also observed when other peroxidases, such as lactoperoxidase, chloroperoxidase and horseradish peroxidase were used for catalyzing BSA iodination in a hydrogen peroxide generating system. No iodination of BSA was obtained with horseradish peroxidase when hydrogen peroxide was added instead of generated so that the inhibitory nature of these drugs could not distinguish between their direct effect on horseradish peroxidase or on hydrogen peroxide generation. However, in lactoperoxidase and chloroperoxidase-catalyzed BSA iodinations in non-H₂O₂-generating systems naproxen had no appreciable inhibitory influence below a 1 millimolar concentration. On another thyroid peroxidase activity, namely its catalyzing influence on the exchange reaction between inorganic iodide and organic iodine in diiodotyrosine, indomethacin and naproxen showed unappreciable effects lower than 1 mM concentrations. Similarly, on thyroid peroxidase and lactoperoxidasecatalyzed deiodination of thyroxine they were ineffective inhibitors. The data suggest that these antiinflammatory drugs are effective inhibitors of iodination reactions but ineffective inhibitors of deiodination reactions.     

Use of an iodide-specific electrode to study lactoperoxidase-catalyzed iodination of l-tyrosine.

An in vitro method employing an iodide-specific electrode for monitoring lactoperoxidase-catalyzed iodination is described. The method utilized lactoperoxidase, potassium iodide, and a glucose--glucose oxidase system for the generation of hydrogen peroxide and l-tyrosine. As iodination of l-tyrosine proceeded, the free iodide concentration in solution decreased and was monitored by an iodide-specific electrode. The iodide electrode was reliable when compared to a 131I-method for measuring free iodide changes in solution. Increasing concentrations of resorcinol, a well-known inhibitor of thyroid peroxidase-catalyzed iodination, in the reaction mixture resulted in graded inhibition of the initial rate of lactoperoxidase-catalyzed l-tyrosine iodination. This in vitro system can be used to assess inhibitory activity of various antithyroid substances.     

Thyroid peroxidase as toxicity target for dithiocarbamates

In vivo ethylenebisdithiocarbamates and ETU are toxic to the thyroid gland. Since the molecular target of these compounds is thought to be thyroid peroxidase (TPO) which catalyzes the transfer of iodine to thyroglobulin, we examined the effect of these compounds on peroxidative activity in Chinese hamster ovary (CHO) cells transfected with the human TPO gene. The activity was inhibited by 50 μM ETU, 5 μM ziram and 5 μM zineb, the last-mentioned effect being irreversible in the absence of iodide. Thiram had no effect. By contrast, the iodinating activity of TPO was blocked only by 5 μM ETU and 50 μM zineb but not by the other compounds. The effect on TPO-catalysed iodination could explain the differences in thyrotoxicity of these compounds in vivo. Received: 13 January 1997 / Accepted: 11 March 1997     

Regulation of thyroid sodium‐iodide symporter in different stages of goiter: Possible involvement of reactive oxygen species

Na⁺/I^? symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d‐5d) or 21 (R1d‐21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time‐dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d‐5d, it was still high in R1d‐21d. On the other hand, iodide uptake was rapidly down‐regulated in R1d‐21d, but not in R1d‐5d, suggesting that the increased TPO activity in R1d‐21d led to increased intraglandular organified iodine (I‐X), which is known to inhibit iodide uptake. Since TGFβ has been shown to mediate some effects of I‐X, we evaluated TGFβ and TGFβ receptor mRNA levels, which were increased in R1d‐21d. Moreover, it has been demonstrated that TGFβ stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H₂O₂ generation in R1d‐21d. Finally, we evaluated the effect of H₂O₂ on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I‐X, TGFβ, NOX4 and increased ROS production.     

Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones

Thyroxine, the main secretory hormone of thyroid gland, is produced from thyroglobulin by thyroid peroxidase/hydrogen peroxide/iodide system. The prohormone T4 is then converted to its potent form T3 by a selenocysteine-containing enzyme iodothyronine deiodinase. Autoantibodies which activate thyroid-stimulating hormone receptor are not under the pituitary feedback control system, and therefore, the uncontrolled production of thyroid hormones leads to a condition called “hyperthyroidism.” The overproduction of T4 and T3 can be controlled by specific inhibitors, which either block the synthesis of thyroid hormone or reduce the conversion of T4–T3. Unique classes of such inhibitors are thiourea drugs, methimazole (MMI), 6-n-propyl-2-thiouracil, and carbimazole suggesting that thione moiety exhibit excellent antithyroid activity. We have carried out biomimetic studies by HPLC assay, which suggested that isochromene-1-thiones exhibit significant antithyroid activity by inhibiting the lactoperoxidase (LPO)-catalyzed iodination, comparable with MMI, and that the inhibitory effects of some of them were found to be much superior to those of MMI. Kinetic studies demonstrate that isochromene-1-thiones inhibit LPO irreversibly. Our inhibition studies suggest that isochromene-1-thiones might be another promising candidate with potential for developing therapeutics for hyperthyroidism. The quantitative structure–activity relationship (QSAR) was developed between the LPO-inhibitory activities of isochromene-1-thiones and their physiochemical properties. The statistical measures, such as r² (0.81), r²adj (0.79), q² (0.73), and F-ratio (39.05), were found to be within the acceptable range.     

Assessment of the biopotency of anti-thyroid drugs using porcine thyroid cells

The effect of six drugs on the uptake and organification of iodide by porcine thyroid cells stimulated with bovine TSH (10 miU/L) has been investigated. The drugs fall into two categories: the peroxidase inhibitors, methimazole (MMI), 2-thiouracil (2-TU) and 3-amino 1,2,4 triazole (3-ATA) and the ionic inhibitors, lithium chloride (LiCl), potassium perchlorate (KC10(4], and sodium iodide (NaI). All the drugs led to a dose-related inhibition of iodide metabolism. The most potent effect on iodide uptake was seen with NaI which inhibited this function by 20% even at 10(-8) mol/l. In contrast, the most potent effect on iodide organification was observed with methimazole which led to a 25% inhibition at 10(-8) mol/l. The concentrations of drug which gave rise to a 50% inhibition of iodide uptake were (mumol/l) 0.26 (NaI), 3.5 (KClO4), 9.7 (2-TU), 15 (MMI), 26 (3-ATA), and 1500 (LiCl). The comparable figures for organification were 0.13 (MMI), 0.18 (2-TU), 0.23 (NaI), 1.2 (3-ATA), 15 (KClO4) and 1300 (LiCl). We conclude that this in vitro system has considerable potential for the assessment of potency and possible bioassay of anti-thyroid drugs of varying structures and sites of action.     

他巴唑对人钠碘转运体mRNA表达的影响

目的探讨他巴唑对人钠碘转运体mRNA表达的影响。方法原代培养甲状腺细胞,测定细胞在他巴唑的作用下人钠碘转运体mRNA的表达量的变化。结果他巴唑能抑制人钠碘转运体mRNA的表达。结论他巴唑可通过人钠碘转运体而发挥抗甲状腺作用。