基于定量构效关系的何首乌毒性单体成分预测

Predicting Toxic Monomer Components in Polygonum multiflorum Based on Quantitative Structureactivity Relationship

目的基于定量构效关系对何首乌中39种化合物进行毒性风险评估,为毒性成分筛选及试验评价提供参考。方法根据母核结构将化合物分为蒽醌、蒽酮及二苯乙烯苷3类。将不同结构式分别导入毒性预测数据库(toxicity estimation software tool,TEST)和化合物毒性预测软件(Derek Nexus)。TEST以大鼠经口毒性半数致死量(LD_(50))和发育毒性为预测终点;Derek Nexus选择除体外和体内致突变性、染色体损伤、致癌性外的所有毒性预测终点(包括肝毒性、肾毒性、心脏毒性、神经毒性、刺激性、光毒性、致敏性等),预测其可能的毒性靶向及相关警示结构。结果大鼠经口毒性LD50:18种蒽醌类化合物的LD50值介于453.5~3574.2 mg/kg之间,16种二蒽酮类单体的LD50值介于125.3~1239.6 mg/kg之间。发育毒性:ω-羟基大黄素和羟基大黄素的预测值最高。毒性靶向及相关警示结构:除6-methyl-1,3,8-trihydroxy-10Hanthracene-9-one外,其蒽醌类化合物均认为存在肝毒性;所有蒽醌类化合物均预测具有光致敏性和皮肤致敏性风险,但警示结构和风险程度存在差异;除2,3,5,4'-四羟基二苯乙烯-2,3-二-O-β-D-葡萄糖苷外,其它二苯乙烯苷类单体提示存在甲状腺毒性风险;大多数二蒽酮类单体存在光致敏性和皮肤致敏性。结论本研究可为何首乌有毒成分筛选、不同成分的毒性靶器官及作用机制提供重要借鉴。

Objective To evaluate the toxicity risks of 39 compounds in Polygonum multiflorum based on the quantitative structural-activity relationship,and provide reference for the screening and experimental evaluation of the toxic components.Methods According to the structures of parent nucleus,the compounds were divided into three categories:anthraquinone,anthrone and stibene glucosides.The structures were imported into Toxicity Estimation Software Tool toxicity estimation software tool,(TEST)and Derek Nexus.Oral toxicity LD50 and development toxicity of rats were the prediction endpoints for TEST All the toxicity prediction endpoints(including liver toxicity,nephrotoxicity,cardiotoxicity,neurotoxicity,irritation,phototoxicity and sensitization)except in vitro and in vivo mutagenicity,chromosomal damage and carcinogenicity were chosen to predict their potential toxicity targets and related alert structures.Results Oral toxicity LD_(50):the LD50 of 18 anthraquinone compounds ranged from 453.5 to 3574.2 mg/kg,while that of 16 dianthrone monomers ranged from 125.3 to 1239.6 mg/kg.Development toxicity:ω-hydroxyemodin and hydroxyemodin demonstrated the highest predictive value,followed by epicatechin and catechin.Toxicity targets and related alert structures:all the anthraquinone compounds were considered hepatotoxic,except for 6-methyl-1,3,8-trihydroxy-10H-anthracene-9-one,and they were predicted with the risks of photosensitization and skin sensitization,while the alert structures varied.All the stibene glucosides,except 2,3,5,4'-tetrahydroxy stilbene-2,3-2-O-β-D-glucoside,showed the risk of thyroid gland toxicity.Most of the dianthrone monomers were photosensitive and skin-sensitizing,while catechin and epicatechin also had the risk of skin sensitization.Conclusion This study may shed light on the screening of toxic components of Polygonum multiflorum,targeted organs and the mechanism of different compound.