Caenorhabditis elegans as model system for rapid toxicity assessment of pharmaceutical compounds
Caenorhabditis elegans as model system for rapid toxicity assessment of pharmaceutical compounds
复制标题
DOI：
10.1016/j.vascn.2004.04.002
复制
发表时间：
2004-11-01
影响因子：
1.9
通讯作者：
van Meel, Jacques C. A.
中科院分区：
文献类型：
--
作者：
Dengg, Marlene;van Meel, Jacques C. A.
前言：模式生物秀丽隐杆线虫被广泛用于遗传学研究，也是生态毒理学的活体生物监测者。在这项研究中，我们调查了C。秀丽隐杆线虫可以代表用于药物化合物的快速初步毒性研究的合适模型。方法：为此，我们使用EGFR激酶抑制剂BIBU 1361、BIBX 1382和无活性化学类似物BIBU 1476。作为毒性评分的第一个参数，我们确定了在化合物存在下野生型秀丽隐杆线虫菌株N2（布里斯托）的致死率。转基因C.使用线虫菌株PC 72（lacZ，热休克蛋白-16（hsp-16）构建体）作为毒性作用的报告生物。PC 72表达β-半乳糖苷酶，当暴露于毒性化合物时，该酶由hsp-16直接诱导。随后通过用X-Gal进行组织化学染色来观察细胞中β-半乳糖苷酶的表达。结果：确定了关于致死率的效力等级顺序：BIBU 1361> BIBX 1382>> BIB 1476。每种化合物的β-半乳糖苷酶诱导具有浓度依赖性，并证明与致死率观察到的效力顺序相同。此外，这些化合物在啮齿类动物中显示出相同的致死性顺序，这是验证的第一个要求。讨论：这些结果表明野生型C。线虫和转基因菌株PC 72都是测定药物化合物毒性的合适模型。这种方法允许化合物毒性的简单和快速的排序，这可能导致进一步的体内试验的更合理的选择。(C)2004年爱思唯尔公司All rights reserved.
Introduction: The model organism Caenorhabditis elegans is widely used for genetic studies as well as a living biomonitor in ecotoxicology. In this study, we investigated whether C. elegans may represent a suitable model for rapid preliminary toxicity studies of pharmaceutical compounds. Methods: For this purpose, we used the EGFR kinase inhibitors BIBU1361, BIBX1382, and an inactive chemical analogue BIBU1476. As a first parameter to score for toxicity, we determined lethality of the wild-type CC elegans strain N2 (Bristol) in the presence of the compounds. The transgenic C. elegans strain PC72 (lacZ, heat shock protein-16 (hsp-16) construct) was used as a report organism for toxic effects. PC72 expresses beta-Galactosidase which is induced by hsp-16 in direct response when exposed to toxic compounds. The expression of beta-Galactosidase in cells was subsequently visualized by histochemical staining with X-Gal. Results: A rank order of potency with respect to lethality was established: BIBU1361>BIBX1382>>BIB1476. The induction of beta-Galactosidase was concentration-dependent for each compound and demonstrated the same order of potency as observed for lethality. Furthermore, these compounds showed the same order for lethality in rodents, the first requirement of validation. Discussion: These results indicate that wild-type C. elegans and the transgenic strain PC72 are both suitable models to determine the toxicity of pharmaceutical compounds. This approach allows for an easy and fast ranking of compound toxicity, which may lead to a more rational choice for further in vivo tests. (C) 2004 Elsevier Inc. All rights reserved.