代谢组学技术在中药研究中的应用

来源:岁月联盟 作者: 时间:2015-05-10

  从目前的研究结果来看,已利用代谢组学的方法对证候动物模型、中药的整体疗效及作用机制、安全性及质量控制等进行了一定的研究,获得了相关“证模型”的生物标志物,为阐释中医证候的生物学本质和病症治疗提供了证据;初步建立了适用于中药多组分、多靶点整体综合效应的药效评价及作用机制研究、安全性评价及质量控制的方法[10-28]。把代谢组学的技术即高分辨、高灵敏度的现代仪器分析技术如NMR、LCMS等和多变量统计分析方法引入中药炮制和代谢产物的研究,可以说是一种延伸,利用这种方法可以发现炮制过程中发生变化的微量活性成分和微量代谢产物,目前开展的工作虽然并不是很多,但已显示了其巨大的潜力[29,32,33]。

  众所周知,中医药认识疾病的方法、理论均缺乏合适的现代科学表达体系,目前仍是一种不能与现代医学相兼容、相通的“语言”。中医药和代谢组学的学术思想方法具有内在相通性:整体性,因而,以代谢组学为主体的系统生物学研究方法可能是认识中医药抽象整体观思想的重要途径。长期以来,对中药药效和作用机制的研究一直沿用化学药物的方法,试图证明哪些成分在起作用,作用于哪个靶点,但是传统用药一般是口服,药物首先要经过胃肠道的吸收才能发挥作用,肠道微生态菌群[34]有可能是一个被忽略的区域,中药有可能通过非直接作用对机体产生效应,引入反映整体观念的代谢组学有可能解开中药作用的神秘面纱。运用代谢组学研究技术,根据不同种属、不同品系动物模型与人的代谢状态的差异,以特征性标记物为参考, 结合传统的中医理论,探索新型中医证动物模型的制作方法将具有十分重要的科学意义。代谢组学方法比传统方法能更快、更准确地发现毒性物质和毒性规律,尤其是多层次、多靶点的综合毒性反应,结合经典的分子生物学手段,将对中药毒性进行整体-局部-系统的全面理解,进而指导中药临床安全用药。代谢组学最成功的应用是英帝国理工大学的Nicholson主持的COMET(consortium for metabonomic toxicology)研究[4],这项研究由辉瑞等5家制药厂资助,旨在利用NMR技术获取具有肝肾毒性的化学品所致的啮齿类动物血液和尿液代谢指纹图谱,建立专家预测系统用以临床前候选化合物的毒性筛选,以降低新药研发的风险和费用。《神农本草经》中记载的“下品”多有毒性,中药所致毒性与化学品是否相同?还是有自己独特的特点?我们能否借鉴COMET研究的经验建立具有中医药特色的专家预测系统?这同样可以降低新药研发的风险和不良反应的发生。应用代谢组学技术对药材不同生长状态下的不同代谢物组作为一个整体来进行考察,用于药材质量控制,注重中药指纹图谱所忽视的分子本质和初生代谢物的影响,更具全面性和优越性,将更进一步解决中药质量控制的复杂性难题,占领传统药物质量技术标准制定的制高点。

  目前,中药代谢组学的研究已取得了喜人的成果,但也应看到,当前代谢组学的研究还处于模式识别和生物标记物鉴定的层次,即无效或有效、对哪些代谢通路产生了影响,如何基于代谢组学研究结果,对中药整体药效作用进行定量表征,阐明中药整体药效作用区别于相应单靶点化学药物的作用特点,如何与经典的形态、功能学相联系,如何与基因组学、转录组学、蛋白质组学整合获得中药作用的全面综合的认识,可能是下一步需要思考的问题,探索性的研究为我们提供了一定的参考[35]。

  代谢组学为广大的从事中药研究的科研工作者提供了崭新的思路与视角,在现有化学、药理或毒理的研究基础之上,引入系统生物学尤其是代谢组学的研究思路,伴随着各种高分辨率、高灵敏度的分析技术、多变量统计分析方法[36]和代谢网络数据库[37]的不断完善及各种技术标准[6,38-41]的建立,有可能搞清楚中药的物质基础、 作用机理、配伍规律、代谢产物和毒副作用等,它有可能使有着几千年历史、以经验为基础的中药治病向以科学的方法和标准为基础的现代化的中药治病转变,从而对中医药事业长远地健康发展产生深远的影响。

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