Köhler P, Bachmann R
Mol Biochem Parasitol. 1981 Dec 31;4(5-6):325-36. doi: 10.1016/0166-6851(81)90064-5.
In vitro incubation of the parasitic nematode Ascaris suum in the presence of 10 microM mebendazole (MBZ) resulted in a complete loss of colchicine binding ability of extracts obtained from the parasite's intestine. Biochemical evidence supported the identification of the colchicine binding receptor in A. suum intestinal extracts as tubulin. This protein was partially purified and found to comprise approximately 0.8% of the soluble intestinal protein. MBZ inhibited colchicine binding to the partially purified tubulin in a competitive manner, the inhibition constant being 4.22 X 10(-6) M. Colchicine binding to porcine brain tubulin was also competitively inhibited by MBZ, exhibiting an inhibition constant of 8.0 X 10(-6) M. [3H]Colchicine binding studies revealed an apparent association constant of A. suum tubulin of 5.88 X 10(4) M(-1). Similar experiments employing [3H]MBZ showed that the extent of MBZ binding to the tubulin up to 10(-5) M was linearly dependent on MBZ concentration. Due to solubility problems the precise association constant for MBZ could not be determined but is apparently less than 10(5) M(-1). In view of the small difference in drug binding abilities between nematode intestinal and mammalian brain tubulin it still remains unclear whether the selective toxicity of MBZ can be solely explained by its interference with the parasite's microtubular system. Further studies reported in this paper suggest that a differential pharmacokinetic behaviour of MBZ between parasite and host may be the essential basis for the difference in drug susceptibility between both biological systems.
在10微摩尔甲苯咪唑（MBZ）存在的情况下，对寄生线虫猪蛔虫进行体外培养，结果发现从该寄生虫肠道提取物中获得的秋水仙碱结合能力完全丧失。生化证据支持将猪蛔虫肠道提取物中的秋水仙碱结合受体鉴定为微管蛋白。该蛋白经部分纯化后，发现约占可溶性肠道蛋白的0.8%。MBZ以竞争性方式抑制秋水仙碱与部分纯化的微管蛋白的结合，抑制常数为4.22×10⁻⁶ M。MBZ也竞争性抑制秋水仙碱与猪脑微管蛋白的结合，抑制常数为8.0×10⁻⁶ M。[³H]秋水仙碱结合研究表明，猪蛔虫微管蛋白的表观缔合常数为5.88×10⁴ M⁻¹。采用[³H]MBZ的类似实验表明，MBZ与微管蛋白结合至10⁻⁵ M的程度与MBZ浓度呈线性相关。由于溶解性问题，无法确定MBZ的确切缔合常数，但显然小于10⁵ M⁻¹。鉴于线虫肠道微管蛋白和哺乳动物脑微管蛋白在药物结合能力上的差异较小，MBZ的选择性毒性是否能仅通过其对寄生虫微管系统的干扰来解释仍不清楚。本文报道的进一步研究表明，MBZ在寄生虫和宿主之间的药代动力学行为差异可能是这两种生物系统对药物敏感性差异的重要基础。
