本文關(guān)鍵詞：Cocktail探針底物法研究白花丹醌對CYP和UGT酶的作用機制　出處：《華東師范大學》2017年碩士論文　論文類型：學位論文

  更多相關(guān)文章： cocktail方法 白花丹醌 CYP酶 UGT酶 藥物-藥物相互作用

【摘要】：隨著中藥和西藥聯(lián)用的普及,它們之間發(fā)生相互作用的報道越來越多,而CYP和UGT酶介導(dǎo)了大部分的中藥-西藥相互作用。本研究在體外建立了 cocktail探針底物法,用于考察化合物對CYP和UGT酶的活性影響,評估潛在的藥物-藥物相互作用,為新藥開發(fā)和臨床安全用藥提供指導(dǎo)。首先,本研究在人和大鼠肝微粒體中分別建立了研究CYP和UGT酶活性的cocktail方法,其中CYP酶主要包括 CYP1A2、CYP2B6/1、CYP2C9/11、CYP2D6/1、CYP2E1 和 CYP3A4/2;UGT 酶主要包括 UGT1A1、UGT1A3、UGT1A6、UGT1A9/PROG 和UGT2B7/AZTG。然后利用此方法評價了多種中藥單體對CYP和UGT酶活性的影響,發(fā)現(xiàn)白花丹醌對CYP酶活性有較強的抑制作用,并探討了作用機制。白花丹醌是從白雪花中提取的具有抗炎和抗過敏等藥理活性的中藥單體,近年來還發(fā)現(xiàn)有較強的抗腫瘤作用。然而白花丹醌在藥物代謝方面的研究甚少,尤其對Ⅰ相CYP酶和Ⅱ相UGT酶的活性影響及作用機制未見報道。本論文發(fā)現(xiàn)白花丹醌對六種CYP酶均有較強的抑制效果,并且為非時間依賴的可逆抑制。酶動力學研究顯示,在人肝微粒體中,白花丹醌對CYP2B6、CYP2C9、CYP2D6、CYP2E1和CYP3A4呈現(xiàn)混合型抑制,而對CYP1A2呈現(xiàn)非競爭性抑制,Ki值分別為1.62μM、2.16μM、1.46μM、0.65μM、0.88μM和 0.15μM;在大鼠肝微粒體中,白花丹醌對CYP1A2和CYP2D1呈現(xiàn)混合型抑制,對CYP2B1、CYP2C11和CYP2E1呈現(xiàn)競爭性抑制,Ki 值分別為 2.64 μM、9.49 μM、9.93 μM、7.85 μM 和 6.28 μM,而對CYP3A2表現(xiàn)出非典型酶動力學抑制。此外,白花丹醌對Ⅱ相UGT酶無明顯抑制效果。綜上所述,本研究在人和大鼠肝微粒體中成功構(gòu)建了檢測CYP和UGT酶活性的cocktail探針底物法,并開展了對多種中藥單體的評價和研究。本論文證明了白花丹醌對人和大鼠肝微粒體中六種CYP酶均有較強的抑制效果,而對UGT酶活性無明顯影響,為進一步開發(fā)及合理使用白花丹醌提供了重要信息。
[Abstract]:With the popularization of traditional Chinese medicine and western medicine, there are more and more reports of interaction between them. However, CYP and UGT enzyme mediated the interaction between traditional Chinese medicine and western medicine. In this study, cocktail probe substrate method was established in vitro. It can be used to investigate the effects of compounds on the activity of CYP and UGT enzymes, to evaluate the potential drug-drug interactions, and to provide guidance for the development of new drugs and clinical safe use of drugs. In this study, a cocktail method was established to study the activities of CYP and UGT in human and rat liver microsomes, in which CYP enzymes mainly included CYP1A2CYP2B6 / 1. CYP2C9 / 11, CYP2D6 / 1, CYP2E1 and CYP3A4 / 2; UGT enzymes mainly include UGT1A1, UGT1A3, UGT1A6. UGT1A9/PROG and UGT2B7 / AZTG.Then the effects of various traditional Chinese medicine monomers on the activities of CYP and UGT were evaluated by this method. It was found that Dandanquinone had a strong inhibitory effect on the activity of CYP and discussed its mechanism. It was a traditional Chinese medicine monomer with anti-inflammatory and anti-allergic activities extracted from Flos Lonicerae. In recent years, it has been found that it has strong anti-tumor effect. However, there are few studies on the drug metabolism of Danquin. In particular, there was no report on the effect and mechanism of the activity of phase 鈪，

本文編號：1413827