摘要
通过虚拟筛选研究四环素的毒性作用,为该药物的安全性评价提供参考数据并为类似结构的化合物毒性评价提供新的参考方法。采用软件预测四环素的毒性作用并通过大数据实验结果进行验证分析,讨论二者之间的契合度。选用以定量毒效模型为基础构建开发的ADMET Predic⁃tor 6.5软件对四环素急性毒性、致突变性、致染色体变异性、致癌性、生殖毒性以及肝脏毒性六个方面进行虚拟预测,并将预测结果与已发表文献实验数据进行比较及综合探讨。结果表明,预测得到该药物的大鼠半致死浓度(LC50)为1092.84 mg/L,远大于软件设置的急性毒性临界值300 mg/L,显示其对大鼠急性毒性作用很低。文献报道其大鼠半致死剂量(LD50)为807 mg/kg,按传统毒性分级方法,该值显示四环素属于低毒药物,该项参数预测结果和实验报道一致。预测认为四环素无致突变性和致癌性,与文献结果契合度较高;预测得到四环素具有致染色体变异性和潜在肝脏毒性,与文献报道基本一致。但预测结果认为四环素不具有生殖毒性,而文献中高剂量四环素对雌雄大鼠均具有生殖毒性,两者契合度较低,可能源于四环素理化性质以及实验条件的影响。研究表明,根据毒效关系建立的预测模型分析四环素的毒性作用具有准确度较高、效率高以及直观性强等特点,可作为类似结构化合物的毒性研究补充方法,且研究结果为四环素的毒性评价提供了数据。
The toxic effects of tetracycline were studied by virtual screening to provide reference data of safety evaluation of this drug and a new reference method for the toxicity evaluation of compounds with similar structures.The toxic effects of tetracycline were predicted by software and verified by big data experimental results,and the fit between the two was discussed.ADMET Predictor 6.5 software was developed based on quantitative toxic effect model.It was used to perform virtual prediction of tetracycline acute toxicity,mutagenicity,clastogenic variability,carcinogenicity,reproductive toxicity and hepatotoxicity,and the prediction results were compared with the experimental data in the published literature and comprehensively discussed.The results showed that the rat median lethal concentration(LC50)of the drug was predicted to be 1092.84 mg/L,which was much greater than the acute toxicity cut-off value of 300 mg/L set by the software,indicating that it had a very low acute toxic effect on rats.It was reported in the literature that the median lethal dose(LD50)in rats was 807 mg/kg.According to the traditional toxicity grading method,this value showed that tetracycline belonged to the low-toxic drug,and the prediction results of this parameter were consistent with the experimental reports.Tetracycline was predicted to be non-mutagenic and carcinogenic,with a high degree of fit to the literature results;the predicted clastogenic variability and potential hepatotoxicity of tetracycline were generally consistent with those reported in the literature.However,it was predicted that tetracycline was not reproductively toxic,while high doses of tetracycline in the literature were reproductively toxic to both male and female rats,with a low fit,possibly due to the effects of tetracycline physicochemical properties as well as experimental conditions.This work showed that the prediction model established according to the toxicityefficacy relationship had high accuracy,high efficiency and strong intuitiveness in analyzing the toxic effects of tetracycline,which could be used as a supplementary method for the toxicity study of compounds with similar structures,and the results of this study provided data for the toxicity evaluation of tetracycline.
作者
赵军杰
程林丽
栾业辉
韩鸿飞
ZHAO Junjie;CHENG Linli;LUAN Yehui;HAN Hongfei(Veterinary Medicine College of China Agricultural University,Beijing 100193,China;National Veterinary Drug Residue Reference Laboratory,Beijing 100193,China;Beijing Key Laboratory of Animal Source Food Safety Testing Technology,Beijing 100193,China)
出处
《饲料工业》
CAS
北大核心
2021年第14期55-59,共5页
Feed Industry
基金
国家重点研发计划“畜禽中典型兽药残留混合污染联合效应”[2018YFC1603005]。
关键词
四环素
毒性预测
定量毒效关系
大数据
比较研究
tetracycline
toxicity prediction
quantitative toxic effect relationship
big data
comparative study
作者简介
赵军杰,硕士,研究方向为兽医药理学和毒理学;通讯作者:程林丽,博士,副研究员,硕士生导师。
