基于CYP450酶系探究古方一贯煎中药物配伍的制毒纠偏作用及机制研究

项目名称： 基于CYP450酶系探究古方一贯煎中药物配伍的制毒纠偏作用及机制研究

项目编号： No.81503554

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王俐琼

作者单位： 上海中医药大学

项目金额： 18万元

中文摘要： 一贯煎是滋阴疏肝著名方剂，滋阴养血药中少佐一味川楝疏肝理气，补肝与疏肝相结合，以补为主，使肝体得养而无滋腻碍胃之虞，且无伤及阴血之弊。全方组方严谨，配伍精当，体现了“肝体阴用阳”的特点，诚为滋阴疏肝之名方。研究证实川楝子及其代谢产物短期应用能够导致急性肝损伤，机制与肝细胞过氧化及CYP450酶活性诱导有关。对于中药的肝毒性临床上被广泛关注，含有肝毒性药物的川楝子组方在一贯煎中使用确未见有导致肝细胞损伤的报道。故推测：一贯煎中诸药降低了川楝子的毒性，机制可能与诱导/抑制CYP450酶系的代谢能力有关。本研究拟用正交设计，选用CYP2E1-/-大鼠和野生大鼠，探究不同配伍肝损的程度及NF-κB、ICAM-l蛋白、caspase-3、bel-2蛋白改变，探寻最佳组合。体外实验观察CYP酶系活性变化，阐明川楝子配伍减毒内在机制，揭示一贯煎的组方思路和作用机制，验证中药配伍制毒纠偏的可行性与科学性。

中文关键词： 一贯煎；P450酶系；川楝子；中药配伍；；制毒纠偏

英文摘要： Yiguanjian is famous Liver Yin prescription, which clever contain poison Toosendan. Various drugs restrict Toosendan toxicity. Studies have confirmed Toosendan and its metabolites may cause acute liver injury after short-term application, the mechanism related with liver cell peroxidation and induction of CYP450 enzyme activity.CYP1A2, CYP2E1 and CYP3A4 (rat CYP3A1) are major subtype member of P450 family involved in drug metabolism and toxicology.Research suggests that Toosendan may inhibit CYP3A activity.Another studies suggest that CYP2E1 is a key enzyme involved of hepatic oxidative stress and lipid peroxidation.moreover,toosendan can enhance the overall capacity of CYP1A2 metabolism.So,we Inferred: Toosendan compatibility with various drugs may be through the induction / inhibition of CYP450 enzymes in metabolic capacity and thus attenuated.Studies involving Toosendan compatibility attenuated, yet Yiguanjian compatibility study report lacked.Therefore, this study intends to use orthogonal design, selection of CYP2E1 - / - rats and wild rats, explore and compatibility after Toosendan correlation and NF-κB and liver injury, ICAM-l protein, caspase-3, bel -2 protein change, exploring the best compatibility Toosendan attenuated.Combined with in vitro experiments, observations CYP2E1 and CYP3A, CYP1A2 activity changes clarify Toosendan compatibility attenuated internal mechanism, further clarify Yiguanjian Prescription ideas and mechanisms of action,in addition,to verify compatibility with medicine through drug manufacturing feasibility and scientific correction to provide a scientific basis for the clinical use of drugs.

英文关键词： yigunjian;CYP450 enzyme;toosendan fruit;compatibility of Chinese herb;toxicity attenuation