An inhibitor of microtubule polymerization
Colchicine, a tubulin inhibitor, which block polymerization of microtubules by binding to tubulin (IC50 = 3.2 μM).
Tubulin is one of several members of a small family of globular proteins. The tubulin superfamily includes five distinct families. To form microtubules, the dimers of α- and β-tubulin bind to GTP and assemble onto the (+) ends of microtubules while in the GTP-bound state.[1] The β-tubulin subunit is exposed on the plus end of the microtubule while the α-tubulin subunit is exposed on the minus end. After the dimer is incorporated into the microtubule, the molecule of GTP bound to the β-tubulin subunit eventually hydrolyzes into GDP through inter-dimer contacts along the microtubule protofilament.[2] This is the GTP cycle which is essential for the dynamic instability of the microtubule.
Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison.[3] So mitosis can be stopped before it completes near the middle of mitosis (specifically metaphase) in the cell cycle. Apart from inhibiting mitosis, colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect in 5 μmol/kg in a mouse model of gouty arthritis and inhibits the deposition of uric acid, a key aspect in the treatment of gout.[4] Side-effects include gastrointestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia and also cause hair loss.[5]
秋水仙碱是一种微管抑制剂，通过与微管蛋白结合（IC50 = 3.2 μM）来阻止微管聚合。微管蛋白是小球蛋白家族的几个成员之一。微管蛋白超家族包括五个不同的家族。为形成微管，α-和β-微管蛋白二聚体与GTP结合并在微管的(+)端组装，而处于GTP结合状态。[1] β-微管蛋白亚单位暴露在微管的正端，而α-微管蛋白亚单位则暴露在负端。在二聚体被并入微管之后，与β-微管蛋白亚单位结合的GTP分子最终通过沿着微管原丝层间的相互作用水解为GDP。[2]这是微管动态不稳定性所必需的GTP循环。秋水仙碱通过与微管的主要组成部分之一的微管蛋白结合来抑制微管聚合。微管蛋白的可用性对于有丝分裂至关重要，因此秋水仙碱有效地作为“有丝分裂毒物”或“纺锤体毒物”起作用。[3]因此，有丝分裂可以在细胞周期的中期（特别是中期）停止之前完成。除了抑制有丝分裂外，秋水仙碱还抑制嗜中性粒细胞的运动和活性，导致小鼠痛风性关节炎模型中5 μmol/kg的净抗炎效果，并抑制尿酸的沉积，这是痛风治疗的关键方面。[4]副作用包括胃肠不适和中性粒细胞减少。高剂量还可能损伤骨髓并导致贫血，并引起脱发。[5]
参考文献:
1. Heald R, Nogales E. "Microtubule dynamics". J. Cell. Sci. 2002,115 (Pt 1): 3–4.
2. Howard J, Hyman A. "Dynamics and mechanics of the microtubule plus end". Nature 2003,422 (6933): 753–8.
3. "Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys)". U.S. Food and Drug Administration.
4. Chen LX, Schumacher HR. "Gout: an evidence-based review". J Clin Rheumatol 2008, 14: S55–62.
5. Colchicine. National Institute for Occupational Safety and Health. Emergency Response Safety and Health Database, August 22, 2008. Retrieved December 23, 2008.
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Animal experiment: |
Mice[3]Specific-pathogen-free 8-week-old male mice are used. Wild-type C57BL/6 mice and NLRP3?/? mice on a C57BL/6 background are used. To examine the effects of Colchicine on NSAID-induced small intestinal injury, vehicle or Colchicine (1 or 3 mg/kg) is administered orally 30 min prior to indomethacin administration. Mice received intraperitoneal injections of sterilized phosphate buffered saline or mouse recombinant IL-1β (0.1 μg/kg) 3 h after indomethacin treatment. Vehicle or Colchicine (1 or 3 mg/kg) is also administered to NLRP3?/? mice before indomethacin administration. The lesion index is evaluated 24 h after indomethacin administration, and examined mRNA and protein expression of inflammasome components 6 h after indomethacin administration. |
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参考文献: [1]. Bonfoco E, et al. Colchicine induces apoptosis in cerebellar granule cells. Exp Cell Res. 1995 May;218(1):189-200. |
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