中国中药杂志

2020, v.45(12) 2954-2959

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基于肝微组织考察何首乌主要单体潜在肝毒性
Study on potential hepatotoxicity of main monomers of Polygonum multiflorum based on liver micro-tissue

汪祺;张茜蕙;文海若;郭浩翔;张乐帅;马双成;
WANG Qi;ZHANG Qian-hui;WEN Hai-ruo;GUO Hao-xiang;ZHANG Le-shuai;MA Shuang-cheng;National Institutes for Food and Drug Control;State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou University;

摘要(Abstract):

该研究旨在建立大鼠原代肝微组织评价体系,并首次采用该体系评价何首乌中主要单体肝毒性作用。实验通过二步原位灌注法对大鼠原代肝实质细胞进行分离纯化,并利用肝实质细胞制备肝细胞微组织,最终采用超低吸附板及倒模法完成体外肝毒性评价体系的搭建。体系建立后,选取何首乌中主要单体成分大黄素-8-O-β-D-葡萄糖苷、大黄素甲醚、大黄酸、大黄素及大黄素型单蒽酮,进行体外肝毒性评价。结果显示,大鼠肝原代细胞采用低吸附板法与模具灌注法可形成肝微组织,并具备较好的肝结构及功能,可用于待测药物长期给药后的肝毒性评价。应用该体系进行实验,结果发现何首乌中的5个待测单体均能明显影响大鼠原代肝微组织的增殖,并且呈现剂量-时间依赖关系,肝毒性作用大小依次为:大黄素型单蒽酮>大黄酸>大黄素>大黄素-8-O-β-D-葡萄糖苷>大黄素甲醚。实验结果进一步提示,大黄素型单蒽酮及大黄酸单体的原型可能为潜在的肝毒性成分,而大黄素-8-O-β-D-葡萄糖苷和大黄素甲醚的代谢产物更具毒性风险。该研究表明,大鼠原代肝细胞微组织模型体系可实现体外细胞长期给药,与长期服用何首乌后导致肝损伤的临床特点相符合,同时实验结果为何首乌的临床应用及毒性成分研究提供了重要参考。
In this study, we aimed to establish a rat liver micro-tissue evaluation system to evaluate the hepatotoxicity of the main monomers in Polygonum multiflorum. Rat primary hepatocytes were isolated and purified by two-step in situ perfusion method to prepare hepatic parenchymal cells. The ultra-low adsorption plate and the inverted model were used to establish an in vitro hepatotoxicity evaluation system. After the system was established, the main monomer components(monanthone with emodin type, rhein, emodin, emodin-8-O-β-D-glucopyranoside, physcion) of P. multiflorum were selected for in vitro hepatotoxicity evaluation. This study showed that the primary cells of the liver can form liver micro-tissues in the low adsorption plate method and the mold perfusion method, with good liver structure and function, which can be used to evaluate the hepatotoxicity of the drug to be tested after long-term administration. The five monomers to be tested in P. multiflorum can significantly affect the proliferation of primary liver micro-tissues in rats in a dose-and time-dependent manner. The hepatotoxic effects were as follows: monanthone with emodin type > rhein > emodin > emodin-8-O-β-D-glucopyranoside > physcion. The results suggested that the emodin-type monoterpene and rhein might be the potential hepatotoxic components, while the metabolites of emodin-8-O-β-D-glucoside and emodin methyl ether showed more toxic risks. The rat primary hepatocyte micro-tissue model system established in this experiment could be used to achieve long-term drug administration in vitro, which was consistent with the clinical features of liver injury caused by long-term use of P. multiflorum. The experimental results provided important information and reference on the clinical application and toxic component of P. multiflorum.

关键词(KeyWords): 大鼠原代肝细胞;肝微组织;何首乌;肝毒性;蒽醌
rat primary hepatocytes;liver micro-tissue;Polygonum multiflorum;hepatotoxicity;anthraquinone

Abstract:

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基金项目(Foundation): 国家自然科学基金项目(81503347,81773874);; 国家“重大新药创制”科技重大专项(2018ZX09735-006)

作者(Author): 汪祺;张茜蕙;文海若;郭浩翔;张乐帅;马双成;
WANG Qi;ZHANG Qian-hui;WEN Hai-ruo;GUO Hao-xiang;ZHANG Le-shuai;MA Shuang-cheng;National Institutes for Food and Drug Control;State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou University;

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