從結構生物學探討疏經活血湯對抗凝血劑之中西藥交互作用

Investigation of Interaction between Shu-Gin-Hwai-Shen-tang and Anticoagulant Warfarin from the Perspective of Structural Biology

林立偉(Li-Wei Lin) ； 翁芸芳(Yune-Fang Ueng) ； 蔡耿彰(Keng-Chang Tsae) ； 許鴻儒(Hung-Ju Hsu) ； 施純全(Chun-Chuan Shih) ； 陳旺全(Wang-Chuan Chen)

《臺灣中醫醫學雜誌》 13卷1期 (2015/03) Pp. 1-11

摘要

中藥複方疏經活血湯主要功用為「疏經、活血、袪濕」，臨床檢驗顯示不直接影響凝血酶原的活性指標（INR）；但西藥抗凝血劑s-warfarin即直接作用抗凝血機制，該藥代謝為細胞色素P450 2C9（CYP2C9）所作用排出。在臨床和動物試驗觀察到疏經活血湯與s-warfarin併用會影響抗凝血活性，此中西藥交互作用改變原先代謝或藥效是有極大危險性。本研究利用計算結構生物學的角度針對疏經活血湯中五個生物活性重要的指標成分：防己諾林鹼、金雀異黃酮、橙皮素、芍藥苷和粉防己分別在細胞色素CYP2C9對s-warfarin代謝作用活性區進行研究。此研究明顯觀察到疏經活血湯的生物活性成分橙皮素和西藥s-warfarin分別在CYP2C9的活性區和異位調節區彼此產生了中藥小分子和西藥小分子交互作用，其兩個分子間主要的作用力來自於氫鍵，進而影響橙皮素在細胞色素CYP2C9對s-warfarin代謝作用活性受其抑制。因此透過結構生物學更清楚闡明生物活性成分橙皮素參與在疏經活血湯併用西藥s-warfarin時增強抑制凝血作用的重要角色。

關鍵字

細胞色素CYP2C9 ； 疏經活血湯 ； 分子模擬

並列摘要

The major function of Chinese compound medicine Shu-Gin-Hwai-Shen-tang comprises channel coursing, blood circulation improvement and clearing damp. Animal study shows that Shu-Gin-Hwai-Shen-tang did not influence the activity index (INR) of prothrombin. However, anticoagulant s-warfarin is directly involved in the anticoagulation mechanism and is mainly metabolized by cytochrome P450 2C9 (CYP2C9). Clinical observations and animal models indicated that the co-administration of Shu-Gin-Hwai-Shen-tang and s-warfarin increased anticoagulation activity of warfarin. The changes of efficacy likely cause great danger in bleeding. The alteration of warfarin metabolism can be one of the potential factor. Our study employs the structural biology approach to investigate the effect of five major biologically active ingredients of Shu-Gin-Hwai-Shen-tang, namely fangchinoline, genistein, hesperetin, paeoniflorin and tetrandrine, on the active site of CYP2C9 for s-warfarin. Docking of ingredients to the active site of CYP2C9 revealed that the interaction is present between hesperetin and s-warfarin at the active regions and allosteric regulation regions of CYP2C9, and the primary force between the two molecules comes from hydrogen bond, which is involved in the inhibition of metabolism of s-warfarin by cytochrome CYP2C9 through hesperetin. Results from structural biology clearly illustrate the important role of hesperetin participating in the enhancement of coagulation inhibition when Shu-Gin-Hwai-Shen-tang is used together with s-warfarin.

並列關鍵字

Cytochrome CYP2C9 ； warfarin ； Shu-Gin-Hwai-Shen-tang ； Molecular Modeling

參考文獻

Yang SH, Yu CL, Chen HY, Lin YH. A commonly used Chinese herbal formula, Shu-Jing-Hwo-Shiee-Tang, potentiates anticoagulant activity of warfarin in a rabbit model. Molecules. 2013; 5;18(10):11712-23

Ktunar, V., Rock, D. A., Warren, C. J., Tracy, T. S., and Wahlstrom, J. L. Enzyme source effects on CYP2C9 kinetics and inhibition, Drug metabolism and disposition: the biological fate of chemicals 2006, 34, 1903-1908.

Kumar, V., Wahlstrom, J. L., Rock, D. A., Warren, C. J., Gorman, L. A., and Tracy, T. S. CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles, Drug metabolism and disposition: the biological fate of chemicals. 2006; 34, 1966-1975

Zhou SF, Zhou ZW, Yang LP, Cai JP. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 ;92(4):414-7.