中医“证-效相关”研究已成为中医药领域的关键科学难题。我们受遗传药理学启示，提出基于细胞色素P450（CYP450）基因多态性探讨证候特征及“证-效相关”的现代内涵。前期研究发现柴胡疏肝散（CSS）较其拆方更显著增强抑郁症肝气郁结证大鼠脑组织BDNF/TrkB表达，其活性成分血药浓度显著高于其他证型。据此推测：抑郁症不同证存在CYP450基因多态性表达谱的差异，肝气郁结证CYP450基因多态性表达谱诱导了CSS“证-效相关”的最佳疗效。本项目拟应用基因分析、分子生物学和细胞生物学等技术，基于体内/外实验，检测抑郁症不同证患者CYP450基因多态性的表达谱，比较CSS对不同证大鼠CYP450基因多态性的影响，在mRNA水平研究CSS对PXR/CAR-CYP3A4途径的影响；为解释抑郁症不同中医证候特征的科学内涵，证实CSS“证效相关”的独特疗效提供理论基础，开辟中医“证-效相关”研究新途径。

The research of “Chinese syndrome-effect correlation” becomes the most important scientific problem of Chinese medicine. Enlightened by pharmacogenetics, we break through the problem based on CYP450 genetic polymorphism. In our previous study, we found Chaihu-Shugan-San significantly enhanced the expression of BDNF/TrkB in brain tissue of rats with depression in Chinese syndrome-Gan Qi Yu Jie than modified formula. The blood concentration of its active components were obviously higher in Chaihu-Shugan-San than other syndrome types. As we have found already, infered that the difference of expression profile of CYP450 genetic polymorphism cause the defferent essence of syndromes in depression. The expression profile of CYP450 genetic polymorphism with Chinese syndrome-Gan Qi Yu Jie induced the best curative effect of “Chinese syndrome-effect correlation” in Chaihu-Shugan-San. This research aims to start to apply genetic engineering, molecular biological and cell biological methods, to determine CYP450, polymorphism of blood from depressive patients with different Chinese syndromes based on experiments in vivo and in vitro, to compare the influence of Chaihu-Shugan-San on CYP450 genetic polymorphism between different Chinese syndromes of depression in rats, to research the influuence of Chaihu-Shugan-San on the pathway of PXR/CAR-CYP3A4. It can provide rationale for scientific connotation of depressive Chinese syndromes, and open up the novel pathway for researches of different Chinese syndromes features of depression and “Chinese syndrome-effect correlation”.

围绕基于证候特征的中医药临床疗效进行“证-效”相关性研究是目前中医药研究领域的关键科学难题。我们以临床常见疾病抑郁症为研究疾病对象，基于中医遗传药理学角度对中医“证-效相关”进行研究。本项目从 CYP450基因多态性检测出发，应用 PCR-RFLP基因分析方法、分子生物学和细胞生物学等技术，从整体水平检测抑郁症不同中医证型患者血浆 CYP450的基因多态性表达谱；从分子水平比较柴胡疏肝散对抑郁症不同证型模型大鼠 CYP450基因多态性的影响；从体外建立 PXR/CAR介导的 CYP3A4诱导研究体系，在mRNA水平基于瞬时共转染报告基因研究柴胡疏肝散对 PXR/CAR-CYP3A4 途径的影响。通过本项目研究显示：1.初步揭示了抑郁症不同证型患者血液中的CYP450基因（CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4）各证型特异相关基因多态性的蛋白表达谱；2.柴胡疏肝散特异性调控了肝气郁结证模型大鼠肝微粒体CYP3A4蛋白表达；3.柴胡疏肝散吸收成分通过PXR/CAR途径调节代谢酶CYP3A4活性水平；4.通过化学计量学分析方法发现5-HT与CREB可作为抑郁症肝气郁结证患者的潜在标志物。本研究为从遗传药理学角度解释抑郁症不同中医证候特征的科学内涵进行了有意义的探索；为辨别证型奠定了方法学基础，为进一步研究抑郁症中医证候关联生物客观指标提供新的分析手段；为从CYP450代谢酶研究角度证实柴胡疏肝散治疗肝气郁结证型抑郁症的独特疗效提供了理论基础，开辟了抑郁症“证-效相关”研究的新途径。