Dvorak Zdenek, Ulrichova Jitka, Weyhenmeyer Roland, Simanek Vilim
Institute of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry Palacký University Olomouc, Hnevotínská 3, 77515 OLOMOUC, Czech Republic.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007 Jun;151(1):47-52. doi: 10.5507/bp.2007.008.
Colchicine has been used to treat gout for centuries. However, owing to its toxicity it displays a variety of side effects. The replacement of colchicine by less toxic but still active derivatives would solve this drawback.
The aim of this study was to examine the cytotoxicity of 17 colchicine derivatives.
Primary cultures of human hepatocytes were the model of choice. Prior to testing, we measured the biochemical parameters of liver donors and the toxicological response of the hepatocytes cultures. For toxicity testing, cells were treated for 24 h with tested compounds in concentrations 1-100 microM. We monitored lactate dehydrogenase (LDH) leakage into the medium, mitochondrial activity (MTT test) and secretion of albumin.
Our data show that LDH and MTT were less sensitive parameters compared to albumin secretion for monitoring the toxicity of colchicine derivatives. Compounds with lower antimitotic activity displayed lowered toxicity.
Since human hepatocytes in culture are quiescent cells, they are not as susceptible to tropolone alkaloids as proliferating cells. Screening for colchicine derivatives with lowered cytotoxicity revealed that 10-O-demethylated compounds might be the substances of choice.
几个世纪以来，秋水仙碱一直用于治疗痛风。然而，由于其毒性，它会表现出多种副作用。用毒性较小但仍具活性的衍生物替代秋水仙碱将解决这一缺点。
本研究的目的是检测17种秋水仙碱衍生物的细胞毒性。
人肝细胞原代培养是首选模型。在测试之前，我们测量了肝脏供体的生化参数以及肝细胞培养物的毒理学反应。为了进行毒性测试，用浓度为1 - 100微摩尔的受试化合物处理细胞24小时。我们监测了乳酸脱氢酶（LDH）向培养基中的泄漏、线粒体活性（MTT试验）以及白蛋白的分泌。
我们的数据表明，与白蛋白分泌相比，LDH和MTT对于监测秋水仙碱衍生物的毒性是不太敏感的参数。抗有丝分裂活性较低的化合物显示出较低的毒性。
由于培养中的人肝细胞是静止细胞，它们不像增殖细胞那样容易受到托酚酮生物碱的影响。对细胞毒性较低的秋水仙碱衍生物进行筛选发现，10 - O - 去甲基化化合物可能是首选物质。
