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研究生:林于菁
研究生(外文):Yu-Chin Lin
論文名稱:槲皮素對Methotrexate 在癌症治療時藥物動力學影響之分子機轉研究
論文名稱(外文):Molecular Mechanism Study of Methotrexate Pharmacokinetics During the Cancer Treatment under the Influence of Quercetin
指導教授:莊聲宏
指導教授(外文):Shin-Hun Juang
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:藥學系博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:111
中文關鍵詞:ABC 多重耐藥性蛋白Methotrexate 耐藥性槲皮素二氫葉酸還原酶β-葡糖醛酸酶
外文關鍵詞:ABC transportersMethotrexate drug resistancequercetin rich herbsDHFRGUSB
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槲皮素(Quercetin)具有多樣藥理活性,主要以配糖體形式廣泛分佈於食用植物中,如 quercetin-O-glucoside 與 quercetin-O-rutinoside (rutin)等。近年來許多研究指出,槲皮素對於治療指數狹窄之藥物具有影響其藥物動力學的特性,例如免疫抑製劑 (cyclosporin),抗癌藥 (methorexate)與強心配糖體(digoxin)等。本研究團隊先前的研究顯示服用富含槲皮素之草藥具有提升 methorexate(MTX)毒性的作用,導致低於 MTX 致死劑量之動物死亡,但其作用機制並不明確。本研究中,探討了富含槲皮素的洋蔥及 rutin 對 MTX 動力學影響之分子機轉。我們研究結果發現,分別併服洋蔥與 rutin,具有顯著增加 MTX 藥物 之 Cmax 與 AUC0-2160 達 1.4 至 2.0倍,而體外研究顯示,含有槲皮素代謝物之血清具有抑制 BCRP 與 MRP 4 等耐藥蛋白功能之作用。此外,發現含有槲皮素代謝物之血清可作為 MTX 耐藥性鼻咽癌細胞株之細胞增敏劑,具有抑制 DHFR 之作用以及逆轉 MTX 抗藥性之活性。本研究發現quercetin-3-O-glucuronide 為血清中之主要代謝產物,且可經由 MTX 耐藥細胞株之細胞膜中過度表現之 GUSB 轉換為槲皮素並通過細胞產生藥裡作用。因此本研究結果提供一種新的治療策略,當併服富含槲皮素之植物可提高 MTX 治療鼻咽癌之療效 。

Quercetin is a pharmacologically active agent, which is widely distributed in edible plants, mainly as glycosides form such as quercetin-O-glucoside and quercetin-O-rutinoside (rutin). Recently, reports indicated that quercetin might interfere the pharmacokinetics of drugs the narrow therapeutic window such as immunosuppressant (cyclosporin), anticancer (mexthorate) and cardiac glycoside (digoxin) and resulting significant adverse effects. Previous our study showed that several quercetin-rich herbs could enhance MTX toxicity and cause animal death under sub-lethal dose, however, the detailed mechanisms remained unknown. In the present study, the effect and molecular mechanisms between MTX and quercetin-rich onion and rutin were investigated. Our results showed that Cmax and AUC0-2160 of MTX were increased by 1.4 fold and 2.0 fold when co-administration with rutin and onion, respectively. Further in vitro studies showed that quercetin-metabolites containing serum could inhibited the functions of BCRP and MRP 4. Furthermore, co-treatment with quercetin-metabolites containing serum could inactivate DHFR activity present in the MTX-resistant cells and might re-sensitize the MTX-resistant NPC cells to MTX treatment. Additional experiments demonstrated that quercetin-3-O-glucuronide a major metabolite of quercetin in the serum could be converted by GUSB over-expressed MTX-resistant cells to quercetin and aid in reversing MTX resistance. In conclusion, our results provide the molecular mechanisms where co-administration of quercetin-containing botanies could enhance MTX efficacy and provide the novel therapeutic strategy to improve the MTX-treatment of NPC.

English Abbreviations................…………….................................................. III
Figure Index..................................................................................................... V
Table Index...................................................................................................... VI
Chinese Abstract.............................................................................................. VII
English Abstract………………………........................................................... IX
Chapter 1. Introduction.................................................................................... 1
1.1 Onion................................................................................................ 8
1.2 Rutin................................................................................................. 11
1.3 Quercetin.......................................................................................... 14
1.4 Methotrexate (MTX) ....................................................................... 17
1.5 Multidrug resistance proteins (MRPs)............................................. 23
1.6 Aldo-keto reductase family 1, member C1 (AKR1C1)…................ 26
1.7 β-glucuronidase (GUSB) ................................................................. 28
Chapter 2. Materials and Methods................................................................... 29
2.1 Cell lines and culture ....................................................................... 29
2.2 Animal experiment………………………………………………... 30
2.3 Antibodies and chemicals................................................................. 30
2.4 Chemicals and reagents.................................................................... 32
2.5 Medium of experiment..................................................................... 36
2.6 Instrument......................................................................................... 37
2.7 Methods…………………………………………………………… 39
2.7.1. Preparation and characterization of OSP................................ 39
2.7.2. Pharmacokinetics studies....................................................... 40
2.7.3. Anti-proliferation effect…………………………………….. 44
2.7.4. Effects of OSP, quercetin and OSPM on BCRP activity…... 45
2.7.5. Effect of OSPM on MRP 4 activity........................................ 46
2.7.6. Dihydrofolate reductase activity assay................................... 46
2.7.7. Preparation of cell membrane………..................................... 47
2.7.8. Western blot analysis ............................................................. 48
2.7.9. Reverse transcription-polymerase chain reaction (RT-PCR) 48
2.7.10. Statistical Analysis............................................................... 49
Chapter 3. Results........................................................................................... 50
3.1 Characterization of OSP.................................................................. 50
3.2 Quantitation of OSP, onion soup and rutin-fed rat serum…….….. 50


3.3 Co-administration of OSP, onion soup or rutin affected the pharmacokinetic parameters of MTX……………………………..
52
3.4 Serum containing quercetin metabolites re-sensitized the MTX-resistant NPC cells to MTX treatment……………………... 53
3.5 Co-treatment weith quercetin metabolites-containing serum blocked biological functions of BCRP and MRP 4……………….. 54
3.6 Effect of OSP extract and quercetin on BCRP activity …………... 55
3.7 Quercetin metabolites-containing serum dose not affect the expression level of ABC-transporters in MTX-resistant cells.......... 56
3.8 Over-expression of DHFR in MTX resistant cell lines...…...…….. 57
3.9 The over-expression of GUSB in the MTX-resistant cell converted Q3G conversion into quercetin…………………..…..... 59
Chapter 4. Discussions..................................................................................... 63
Chapter 5. Reference........................................................................................ 69


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