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頁籤選單縮合
題名 | 常用中藥對人類細胞色素P450影響之研究=Investigation of Effect of Commonly Used Traditional Chinese Medicine on Human Cytochrome P450s |
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作者 | 翁芸芳; | 書刊名 | 中醫藥年報 |
卷期 | 3 2014.12[民103.12] |
頁次 | 頁(44)3-(44)25 |
分類號 | 414.5 |
關鍵詞 | 常用中藥; 萃取物; 人類; 細胞色素P450; 抑制作用; Commonly used traditional Chinese medicine; Extract; Human; Cytochrome P450; Inhibition; |
語文 | 中文(Chinese) |
中文摘要 | 研究目的:對於中草藥及天然物衍生藥物在亞洲及歐、美等地被廣泛的使用或積極科學化研發中。由細胞色素 P450(P450, CYP)組成之單氧.系統是藥物氧化代謝之主要.系統,CYP3A4 是人肝中含量最高的 P450 成員,陸續有報告顯示中藥材成分具有調控藥物代謝.的能力,進而可能改變藥物的藥理活性或毒性。在國人常用中藥材前 10 名中,對枸杞(Lycii Fructus, Lycium chinese)、大棗(Zizyphi Fructus, Ziziphus jujuba)、茴香(Foeniculi Fructus, Foeniculum vulgare),雖已有報告說明其中數種藥材對 P450 造成誘導或抑制作用,但多為對鼠 P450 影響之探討,對多種人類 P450 之影響及比較並不完全清楚。其他中藥包括:延胡索(Corydalis Rhizoma, Corydalis yanhusuo)、薏苡仁(Coix seed, Coix lachryma)、山藥(Dioscoreae Rhizoma, Dioscorea spp.)雖非前 10 名,但亦為常用中藥。因此這一年期計畫針對其中 6 種常用藥材對人類 P450 之影響進行研究,探討常用中藥萃取物對人類 P450 之體外作用及代謝對此交互作用之影響。這些研究對於傳統中藥的科學化以及民眾用藥安全都將有幫助。 研究方法:以大腸桿菌表達包括:CYP1A2、CYP1B1、CYP2A6、CYP2C9、CYP2D6、CYP2E1、CYP3A4 等人類 P450,製備枸杞、茴香、大棗、薏苡仁、延胡索藥材之 50%酒精萃取物、山藥製劑之甲醇及 50%酒精萃取物。測定表達之人類 P450之含量及代謝活性。製備萃取物,測定對 P450 之作用。 結果與討論:表達的人類 P450 包括:CYP1A2、CYP1B1、CYP2A6、CYP2C9、CYP2D6、CYP2E1、CYP3A4。製備枸杞、茴香、大棗、薏苡仁、延胡索藥材之 50%酒精萃取物,得到產量分別為 0.02~0.46(萃取物/藥材或萃取製劑,克/克)、山藥製劑之甲醇及 50%酒精萃取物,得到產量分別為 0.2~0.48(萃取物/藥材或萃取製劑,克/克)。枸杞 50%酒精萃取物對上述人類 P450 的標誌受質代謝活性在濃度高至 1 mg/mL 不造成影響或抑制作用小於 50%。而薏苡仁及茴香酒精萃取物因對dimethyl sulfoxide 溶解度較低,在反應中最高分別達 100 及 240 μg/mL。抑制作用中以重組人類 CYP1B1 之活性受茴香抑制之 IC50 值最小,酵素動力學分析顯示Ki 及 KI 值分別為 3.8 ± 0.9 及 7.6 ± 2.3 μg/mL。CYP1A2 之活性受茴香、延胡索之50%酒精萃取物、山藥之甲醇萃取物的抑制影響。CYP2C9 之活性受茴香的抑制影響,經代謝後抑制作用降低,層析結果說明經 CYP2C9 CYP3A4 代謝後有代謝產物產生。在 3 家藥廠製備之山藥萃取製劑之甲醇萃取物中,有一家的製劑之萃取物具抑制 CYP2C9 活性之作用。CYP2D6 受延胡索之酒精萃取物抑制。CYP3A4受延胡索之 50%酒精萃取物抑制。但在預反應(pre-incubation)處理,預反應之進行是將萃取物與人類細胞色素 P450 在有 NADPH 的環境下反應 10 分鐘後,再進行活性測定。這些抑制作用受預反應代謝作用之影響不盡相同。 |
英文摘要 | AIM: Since traditional Chinese medicines (TCMs) and/or herbal medicines have been widely used, great notice has been focused on the drug interaction due to the functional alteration of drug-metabolizing enzymes by TCMs and natural products. Cytochrome P450 (P450, CYP)-dependent monooxygenase system locating at cellular endoplasmic reticulum membrane is the main enzyme system responsible the oxidative metabolism of xenobiotics including drugs and natural products. The aims of this one-year grant are to determine the effects of commonly used TCMs on human P450s and to characterize the effect of metabolism on the interaction between TCMs and human P450s. METHODS: Recombinant human P450s were expressed in Escherichia coli DH5 Ethanol (50%) extracts of Lycii Fructus, Zizyphi Fructus, Foeniculi Fructus, Corydalis Rhizoma, Coix seed were prepared. Methanol and ethanol (50%) extract of Dioscoreae Rhizoma were prepared. Effects of extracts on P450 activities and the herb-P450 interaction affected by metabolism were investigated. Chromatographic analyses of the extracts were performed. RESULTS & DISSCUSSION: Recombinant human P450s were expressed in Escherichia coli DH5 The yield of ethanol (50%) extracts prepared from Lycii Fructus, Zizyphi Fructus, Foeniculi Fructus, Corydalis Rhizoma, Coix seed were 0.02~0.46 g/g. The yield of the methanol and ethanol (50%) extract of the powdered Dioscoreae Rhizoma decoction were 0.02~0.48 g/g powdered decoction. The solubility of extracts of Coix seed and Foeniculi Fructus in dimethyl sulfoxide was lower than 100 and 240 g/mL, respectively. Among the effects determined, the ethanol extract of Foeniculi Fructusinhibited CYP1B1 activity with a smallest IC50 value. This inhibition had Ki and KI of 3.8 ± 0.9 and 7.6 ± 2.3 g/mL, respectively. Without pre-incubation, CYP1A2 activity was inhibited by the ethanol extracts of Foeniculi Fructus and Corydalis Rhizoma, and the methanol extract of the powdered Dioscoreae Rhizoma decoction. CYP2C9 activity was inhibited by the ethanol extract of Foeniculi Fructus. Chromatographic analyses showed the formation of metabolite(s) by CYP2C9 and CYP3A4. Among three pharmaceutical companies, the methanol and ethanol extracts of the powdered Dioscoreae Rhizoma decoction prepared from one of them showed inhibitory effect on CYP2C9 activity. CYP2D6 activity was inhibited by Corydalis Rhizoma extract. CYP3A4 activity was inhibited by the ethanol extract of Corydalis Rhizoma extract, the methanol extract of the powdered Dioscoreae Rhizoma decoction. These inhibitory effects were differentially affected by pre-incubation. |
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