利用秀丽隐杆线虫初步评价药物急性毒性

Preliminary acute toxicity assessment of pharmaceutical compounds by Caenorhabditis elegans

目的考察秀丽隐杆线虫(C.elegans)是否适合作为一个快速初步评价药物急性毒性的模型。方法采用秀丽隐杆线虫野生型N2和突变型glp-4;sek-1线虫对药物毒性进行评估,通过监测在相同染毒体系中的死亡率,判断2种线虫对药物毒性的敏感度。对4大类抗感染抗生素和3种抗肿瘤药物的毒性进行评估。测定染毒72 h后不同药物的LC50值。结果红霉素对N2和glp-4;sek-1线虫的LC50(72 h)分别为250和120 mg.L-1;阿奇霉素对N2和glp-4;sek-1线虫的LC50(72 h)分别为411和286 mg.L-1,glp-4;sek-1线虫国较N2线虫对药物毒性更敏感,因此,采用glp-4;sek-1线虫作为药物评价体系。本实验中,大环内酯类药物LC50(72 h)为100～300 mg.L-1、四环素类为300～400 mg.L-1、氨基糖苷类药物为400～2500 mg.L-1、青霉素类大于2000 mg.L-1和抗肿瘤药物为40～60 mg.L-1。线虫与小鼠相比,对药物毒性更敏感,并且大部分药物在线虫评价体系中呈现的毒性大小,与小鼠评价体系相类似,即两种评价系统具有较好的正相关性。结论秀丽隐杆线虫合适用于药物急性毒性的初步评价,能够简便快速地判断药物毒性范围。

OBJECTIVE To investigate whether C.elegans may represent a suitable model for rapid preliminary acute toxicity studies of pharmaceutical compounds.METHODS Sensitivity of the wild-type C.elegans strain N2 and mutant-type strain glp-4;sek-1 in the presence of the same drugs was determined by lethality.The half lethal concentration（LC50）（72 h） of four types of antibiotics and 3 anti-tumor drugs was measured.RESULTS LC50 of erythromycin on N2 strain and glp-4;sek-1 strain was 250 and 120 mg·L-1.LC50 of azithromycin on N2 strain and glp-4;sek-1 strain was 411 and 286 mg·L-1.glp-4;sek-1 Strain was more sensitive than N2 strain,so glp-4;sek-1 strain was used as model system for toxicity assessment of drugs.LC50（72 h） was 100-300 mg·L-1 for macrolides,300-400 mg·L-1 for tetracycline,400-2500 mg·L-1 for aminoglycosides and 40-60 mg·L-1 for anti-tumor drugs.Compared with mice,C.elegans was susceptible to the toxicity of drugs.Also,toxicity of most tested drugs presented in C.elegans system was similar to that of the mouse system,indicating that the two evaluating systems had a good positive correlation.CONCLUSION C.elegans is a suitable model system to determine the toxicity of drugs.This approach allows for an easy and fast ranking of compound toxicity,which may facilitate a more rational choice for further in vivo tests.