基于肝癌患者CYP2E1活性增高研究CYP2E1特异性抑制剂

肝癌发生与亚硝胺、肝炎等有关，CYP2E1具有代谢活化亚硝胺作用和致炎作用。我们前期研究证明，肝癌患者CYP2E1代谢亚硝胺活性明显增高且与生存期呈现明显负相关，大鼠CYP2E1先天活性与亚硝胺诱发的肝纤维化和肝癌具有因果关系，CYP2E1非特异性抑制剂则可抑制之。据此提出假说“CYP2E1活性增高可能是肝癌等发生发展的重要原因”。.本研究主要对CYP2E1特异性抑制剂的发现和应用的关键基础进行研究。经计算机辅助设计、抑制功能筛选、结构优化等发现CYP2E1特异性抑制剂；根据特异性抑制剂与不同CYP2E1突变型重组体相互作用差异，确定抑制剂与受体结合的关键氨基酸位点及亲和力；应用亚硝胺等所致大鼠肝炎、肝纤维化和肝癌模型，探讨特异性抑制剂的防治作用；应用细胞模型和转基因动物，探讨特异性抑制剂的防治作用机制；对特异性抑制剂进行初步安全性评价。最终发现CYP2E1特异性抑制剂，并评价其应用前景。

Nitrosamines and hepatitis virus both are the recognized risk factors for hepatocellular carcinoma (HCC). CYP2E1 is of particular interest because of its involvement in the metabolic activation and inflammation.Our previous studies indicated CYP2E1 activity was increased in HCC patients and CYP2E1 activity was negatively correlated with overall survival, moreover, higher CYP2E1 innate activity had a causal relationship with hepatofibrogenesis and HCC induced by diethylnitrosamine in rats, which could be prevented by non-specific inhibitor of CYP2E1. Accordingly, we hypothesize that increased CYP2E1 activity might play an important role in the development and progression of HCC..This study focuses on the key basis of the discovery and application of CYP2E1 specific inhibitors. Discovery for CYP2E1 specific inhibitors is based on computer aided design, structure optimization and inhibition screening. Differences in the interaction of specific inhibitors with different CYP2E1 mutant recombinant will be investigated to determine the key amino acid sites and the affinity of the inhibitor binding. Hepatitis, hepatofibrogenesis and HCC model induced by nitrosamine in rats will be applied to study the effect of specific inhibitor on prevention and treatment. Cell model and transgenic animal will be used to explore the mechanism on prevention and treatment of specific inhibitors. Finally, preliminary safety as well application prospects of specific inhibitors will be evaluated.