摘要临床上服用何首乌致急性肝损伤的病例目前一直存在，近年来逐渐被重视，患者的症状分别表现为轻重度黄疸、急慢性肝炎、肝功能异常等，虽然患者在停止使用相关制剂后，症状都有所改善，但是其用药安全仍引起广泛关注。本研究对生何首乌醇提物进行毒理考察，将三个不同浓度梯度的何首乌醇提物对小鼠灌胃28天，收集血清和肝脏组织，运用组织病理学检查、生理生化检测和基于核磁共振的代谢组学分析等方法，全面探究何首乌醇提物对小鼠内源性小分子代谢物在机体内代谢水平的影响，分析何首乌的药物肝损伤(drug induced liver injury -DILI)机制。42470

实验揭示，给药组小鼠在28天灌胃之后，与对照组相比，肝组织细胞存在炎症，细胞内水肿，CAT、SOD水平下降，肝脏发生氧化应激反应；血清中的AST、ALT指标也有一定程度升高，肝脏组织存在被破坏和坏死的情况。利用基于核磁的代谢组学研究肝脏中代谢化合物含量变化的趋势，结合代谢通路可以进一步发现：给药组小鼠机体内的氧化应激反应进一步的导致了其能量代谢的紊乱、氨基酸代谢和嘌呤、嘧啶代谢的异常。并且从不同剂量给药组小鼠与对照组两两比较之后得到的Fold change plot中，可以发现给药组小鼠的肝损伤，几乎无明显的剂量依赖性。其中中剂量组的小鼠与对照组之间的代谢化合物变化趋势几乎不显著，可能是何首乌其中的保护性药效成分发挥了作用，当小鼠机体内已经存在一定程度的肝损伤，“损有余而补不足”使得何首乌本身的肝毒性表现的不明显，转而凸显其活络血液、解毒益肝的药效，使得小鼠自身的机体保护和修复能力大大增强。

何首乌是一种具有滋补益处的中药，并且被频繁使用，但是由于中药使用没有科学的明确的使用规格和条件，被错误使用的几率大大提高；且目前对于何首乌药效和毒性之间的转换关系仍旧不是特别清楚，所以在何首乌的使用过程中要注意用药的剂量和时间，以及不同个体对药物的耐药性和敏感程度。

关键词  何首乌 肝损伤 代谢组 核磁 安全剂量 药效 毒效 转换关系

毕业论文设计说明书外文摘要

Title  NMR-based metabonomics approach to study the conversion relations of efficacy and toxicity of Polygonum multiflorum                   

Abstract

Objective: As a kind of commonly used TCM, Polygonum multiflorum(He Shou Wu)is now frequently questioned for its liver toxicity，raising lots of social concerns. This project use 1H NMR metabonomics approach to study the mechanism of PM induced liver toxicity, find the conversion relations of its efficacy and toxicity, and give some suggestions for rational use of PM . 

Methods: The ethanol(50%) extracts of PM was diluted with water into three different concentrations(15g/kg、10g/kg、5g/kg) , and was gavage administered to rats which were randomly pided into four groups(H-High、M-Medium、L-Low、C-Control)for 28 days. The serum and liver samples were collected and then subjected for histopathology observation、biochemical measurement and 1H NMR-based metabolomics research.

Results: Compared with the control rats, metabolic pathways of low dosage administered rats were revealed to be altered by pattern analyses of plasma NMR data, which was further correlated with serum biochemistry. Cross-validated scores mean trajectory derived from PLS-DA of NMR spectra demonstrated that PM induced liver injury is not dose-dependent. Detailed analysis of the altered metabolite levels indicated that low dosage group rats exhibited significant disturbance in energy metabolism、amino acid metabolism、protein degradation、purine metabolism and pyrimidine metabolism. The results confirmed the mechanism of PM liver toxicity and the relationships of the efficacy-toxicity conversion to some extent. Further work should be performed to study PM drug induced liver injury (DILI).