呋喃类化合物广泛分布于各种中药中，该类成分可能被某些P450酶亚型代谢活化并导致酶机制性失活。乌药醚内酯（LDR）是利用前期建立的基于溴元素衍生化的分析平台在乌药中筛查出的可被代谢活化的主要呋喃倍半萜类成分。LDR会使CYP2C9机制性失活，可能与呋喃环被代谢活化有关，但具体机理尚不明确。我们提出科学假设：LDR的呋喃环经代谢活化对CYP2C9的亲核基团发生共价修饰，导致其活性被不可逆抑制，继而可能会与由CYP2C9代谢的药物发生相互作用。本项目在前期基础上，将重点研究LDR的亲电性代谢物共价修饰CYP2C9的化学机制，同时探明以CYP2C9作为主要代谢酶的药物与LDR的相互作用情况以验证LDR对CYP2C9的抑制作用。本课题系统阐明LDR引发CYP2C9机制性失活的分子机理，为研究可被代谢活化的呋喃类化合物产生P450酶抑制的机制，及临床与之相关的药物之间相互作用提供共性研究思路与方法。

Furanoids occur in a wide range of herbs, and many of them have been documented as mechanism-based inactivators of cytochromes P450. By application of our developed bromine-based analytical platform, Linderane (LDR) was detected as one of the main furan-containing sesquiterpene components in Lindera aggregata (Sims) Kosterm, which can be metabolic activated. Our early study demonstrated that LDR acted as a mechanism-based inactivator of CYP2C9, and that the enzyme inactivation was associated with the metabolic activation of furan ring of LDR, whereas the definite mechanism involved was not yet clear. We proposed our hypothesis: the nucleophilic groups of the active site of CYP2C9 were covalently modified via metabolic activation of the furan ring，as a result that potential drug-drug interaction (DDI) between LDR and substrates of CYP2C9 may occur. As a continuous work, we will focus on the chemical mechanism of the covalent modification of CYP2C9 by reactive metabolites of LDR; as well as DDI between LDR and substrates of CYP2C9 to further verify the effect of enzyme inactivation by LDR. This application allows us to elucidate the molecular mechanism of CYP2C9 inactivation by LDR and provides common research ideas and methods for investigation of the mechanism of mechanism-based inactivation of P450 enzyme and DDI in clinical caused by furan-containing compounds which can be metabolic activated.