Nagasaka A, Hidaka H
J Clin Endocrinol Metab. 1976 Jul;43(1):152-8. doi: 10.1210/jcem-43-1-152.
The mechanism of inhibition of human thyroid iodide peroxidase (TPO) by 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) used in the therapy of hyperthyroid patients was studied in vitro. The inhibition of TPO by MMI was not restored either by dialysis or by dilution, but the inhibition by PTU was restored by both treatments. PTU interacted directly with the product of TPO action (oxidized iodide) in the reaction mixture without significantly affecting TPO activity. MMI interacted directly with TPO and inhibited enzyme activity, rather than interacting with the product (oxidized iodide). The inhibition was irreversible with MMI, but reversible with PTU. The concentrations of PTU and MMI producing 50% inhibition of TPO were 2 x 10-6m and 8 x 10-7m, respectively, 2-Mercaptoimidazole inhibited TPO reversibly but 1-methylimidazole and imidazole did not. Both the methyl and mercaptoresidues in MMI moiety are thought to be essential to its irreversible inhibition of TPO. The in vivo effect of MMI and PTU on TPO activity was also studied. TPO activities in the thyroid homogenate of rats to which MMI (2 mg per rat) or PTU (10 mg per rat) had been administered intraperitoneally were determined before and after dialysis against buffer. TPO activity in the PTU treated thyroid homogenate was significantly lower than that in the control before dialysis, but the activity was restored to the control value after dialysis. On the contrary, TPO activity in the MMI treated thyroid homogenate was significantly lower than that in the control and was not affected by dialysis. These data may explain why MMI is a more potent inhibitor of iodination than PTU and may fit the clinical results observed when hyperthyroid patients are treated with these agents.
在体外研究了用于治疗甲状腺功能亢进患者的6-丙基-2-硫脲嘧啶（PTU）和1-甲基-2-巯基咪唑（MMI）对人甲状腺碘化过氧化物酶（TPO）的抑制机制。MMI对TPO的抑制作用无论是通过透析还是稀释都不能恢复，但PTU的抑制作用通过这两种处理均可恢复。PTU在反应混合物中直接与TPO作用的产物（氧化碘）相互作用，而对TPO活性无明显影响。MMI直接与TPO相互作用并抑制酶活性，而不是与产物（氧化碘）相互作用。MMI的抑制作用是不可逆的，而PTU的抑制作用是可逆的。产生50%TPO抑制作用的PTU和MMI浓度分别为2×10-6m和8×10-7m，2-巯基咪唑可逆地抑制TPO，但1-甲基咪唑和咪唑则不能。MMI部分中的甲基和巯基残基被认为对其不可逆抑制TPO至关重要。还研究了MMI和PTU对TPO活性的体内作用。在对缓冲液进行透析前后，测定了腹腔注射MMI（每只大鼠2mg）或PTU（每只大鼠10mg）的大鼠甲状腺匀浆中的TPO活性。PTU处理的甲状腺匀浆中的TPO活性在透析前显著低于对照组，但透析后活性恢复到对照值。相反，MMI处理的甲状腺匀浆中的TPO活性显著低于对照组，且不受透析影响。这些数据可以解释为什么MMI比PTU是更强的碘化抑制剂，并且可能与甲状腺功能亢进患者用这些药物治疗时观察到的临床结果相符。
