臺灣博碩士論文加值系統

橘黴素(Citrinin，CIT)為紅麴菌發酵在生成紅色素時產生的代謝產物，是一種具有腎臟及肝臟及致畸胎毒性的真菌毒素。因為現在市面上具有養生概念之紅麴相關產品越來越多，導致其中可能含有橘黴素的風險也隨之提高。因此，本論文應用基質輔助雷射脫附游離/飛行時間質譜儀(MALDI-TOF MS)開發出具有低成本，且可快速篩選CIT毒素的分析方法。
本方法中的前處理只需要以約2 mL的溶劑萃取分析物後離心，取上清液即可以MALDI-TOF/MS來進行偵測。以α-CHCA為基質時，標準品的偵測極限為1 ppm，在基質中添加α-環糊精後，提高10倍偵測極限到100 ppb。在真實檢體小麥及紅麴薄餅的偵測極限可達200 ppb；在真實檢體紅麴米及紅麴膠囊的偵測極限可達1 ppm。此法所需成本很低（NT≦10）且偵測時間小於1分鐘，可節省不必要的材料及時間的浪費，相當符合當前綠色化學的環保概念。

Citrinin (Citrinin, CIT) , a kind of mycotoxins with teratogenic toxicity and harmful to kidney and liver, is a metabolite of Monascus fermentation during generating red pigment. Since more and more health-related Monascus fermentation products are introduced to the market, the risk of citrinin contaiminations may increase. Therefore , I develope a low-cost, and rapid screening method to detect CIT by using matrix-assisted laser desorption ionization / time of flight mass spectrometry (MALDI-TOF MS) .
On this method, the pretreatment process requires only about 2 mL solvent to extract the sample centrifuged, the supernatant can be detected directly by MALDI-TOF/MS. When using α-CHCA as matrix, the detection limit is 1 ppm for standard, after adding α-cyclodextrin in the matrix, the limitation of detection can be improved 10 times to the 100 ppb. In the real specimen of wheat and red yeast pancake the detection limit can reach to 200 ppb ; for red yeast rice and red yeast capsules the detection limit can reach to 1 ppm. This method requires very low cost (NT ≦ 10) for each sample and the detection time is less than one minute. By this method, I may avoid unnecessary waste of materials and time consuming. This is in line with current environmental protection concept of green chemistry.

目錄
中文摘要…………………………………………..…………………….…….......................I
英文摘要……………………………………………………………................. ..........II
誌謝.......................................... ..........III
目錄…………………………………………………………………................ ............IV
表目錄…………………………………………………..………...….……....................VII
圖目錄..………………………………………………………………....……..................VIII
第一章 緒論…………………..…….………………....…….…...……………...............1
1.1 前言……….……………………….……………..…….....…..…............1
1.2 橘黴素(Citrinin)與紅麴的簡介………………………………….............2
1.3 橘黴素(Citrinin)檢測技術……………………………….....................7
1.4 基質輔助雷射脫附游離飛行時間質譜法……........................13
1.4.1 MALDI的簡介…..…...……..……………………............13
1.4.2 MALDI的發展…….............................13
1.4.3 MALDI的樣品配製…..…...……..……………………........14
1.4.4 基質的特性………………………………………………..............16
1.4.5 MALDI 離子形成的機制………………………………...........19
1.4.6 飛行時間質量分析儀的原理……………………………..........21
1.4.7 MALDI-TOF MS的特點…………………………………...........27
1.5 研究動機與目的..…...……..……………………………………..................28
第二章 材料與方法……………..…….………………....…….…...………….............31
2.1 實驗材料..…...……..…………………………………………….............31
2.1.1 實驗藥品…..……………………………………………..............31
2.1.2 實驗樣品…..……………………………………………..............33
2.1.3 儀器設備…..……………………………………………..............33
2.2 藥品配製..…...……..……………………………………………....................34
2.2.1 基質溶液的配製………………………………………….............34
2.2.2 鹽類溶液的配製………………………………………….............36
2.2.3 α-環糊精溶液的配製………………………..........37
2.2.4 標準品的配製……………………………………………..............37
2.3 食品樣品的萃取…………………………………………………................38
2.3.1 食品樣品的毒素添加……………………………………............38
2.3.2 食品樣品萃取……………………………………………..............38
2.4 MALDI 配製與偵測條件……………………………………….....................40
2.4.1 MALDI 樣品的配製……………………………………............40
2.4.2 MALDI-TOF MS 的操作條件……………………...........41
第三章 結果與討論…………………………………….............................42
3.1 最佳的分析條件………………………….........................42
3.1.1 基質的選擇…………………………......................42
3.1.2 增加分析的靈敏度……………….....................58
3.2 真實樣品的檢測…………………………................................68
第四章 結論.…………………..………………………...…………..……….................83
參考文獻………..……………………………….………...……………..…...................84
表目錄
表一 台灣食品之橘黴素(Citrinin)含量上限..……………….…..…...........6
表二 日本食品之橘黴素(Citrinin)含量上限…..………………..……...........6
表三 各種檢測Citrinin方法的比較….….….……..……..…...…...........11
表四 常用的基質結構與適用的分析物和有效的雷射波長….….…............18
表五 MALDI-TOF MS 操作參數設定….……..…...…...................41
表六 不同基質與不同濃度的 CIT 毒素之訊號….….….……..……...........57
表七 不同濃度 CIT 添加五種鹽類的訊號及強度….….….……..…..........63
表八 本實驗檢驗方法與衛生署99年公告檢驗方法的結果比較……...........71
圖目錄
圖一、橘黴素(citrinin)的化學結構式及其UV-Vis吸收圖...............2
圖二、紅麴的製作流程..........................................3
圖三、MALDI-TOF MS的簡圖：(a) linear (b) reflectron……………...26
圖四、固體基質α-CHCA之MALDI-TOF質譜圖.........................44
圖五、固體基質 α-CHCA 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm(c) 0.1 ppm 進行偵測之 MALDI-TOF 質譜圖...................44
圖六、固體基質2,4-DHB之MALDI-TOF質譜圖…………………………..............46
圖七、 固體基質 2,4-DHB 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm 進行偵測之 MALDI-TOF 質譜圖…………………………………...............46
圖八、固體基質2,5-DHB之MALDI-TOF質譜圖…………………………..............48
圖九、 固體基質 2,5-DHB 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm (c) 0.1 ppm進行偵測之 MALDI-TOF 質譜圖……………………...........48
圖十、固體基質2,6-DHB之MALDI-TOF質譜圖…………………………..............50
圖十一、固體基質 2,6-DHB 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm(c) 0.1 ppm 進行偵測之 MALDI-TOF 質譜圖……………..............50
圖十二、Et3N-α-CHCA之MALDI-TOF質譜圖……………………………..............52
圖十三、Et3N-α-CHCA 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm(c) 0.1 ppm 進行偵測之 MALDI-TOF 質譜圖………………………..........52
圖十四、Citrate-Capped AuNPs之MALDI-TOF質譜圖……………………........54
圖十五、Citrate-Capped AuNPs 與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm(c) 0.1 ppm 進行偵測之 MALDI-TOF 質譜圖……………........54
圖十六、單純鋁箔基質之MALDI-TOF質譜圖……………………………...............56
圖十七、鋁箔基質與不同濃度的 CIT 標準品：(a) 10 ppm (b) 1 ppm 進行偵測之 MALDI-TOF 質譜圖………………………………………......................56
圖十八、CIT 標準品 10 ppm 與 α-CHCA 混合後分別添加不同的鹽類： (a)、(e)未添加鹽類溶液 (b) 添加LiCl (c) 添加 NaCl (d) 添加KCl (f) 添加RbCl (g) 添加CsCl 進行偵測之 MALDI-TOF 質譜圖................59
圖十九、CIT 標準品 1 ppm 與 α-CHCA 混合後分別添加不同的鹽類： (a)、(e)未添加鹽類溶液 (b) 添加LiCl (c) 添加 NaCl (d) 添加KCl (f) 添加RbCl (g) 添加CsCl 進行偵測之 MALDI-TOF 質譜圖................61
圖二十、CIT 標準品 0.1 ppm 與 α-CHCA 混合後分別添加不同的鹽類： (a)、(e)未添加鹽類溶液 (b) 添加LiCl (c) 添加 NaCl (d) 添加KCl (f) 添加RbCl (g) 添加CsCl 進行偵測之 MALDI-TOF 質譜圖.............62
圖二十一、α-環糊精的化學結構圖………………………………………….................65
圖二十二、α-CHCA的化學結構圖…………………………………………….................65
圖二十三、α-CHCA 添加α-環糊精之 MALDI-TOF 質譜圖……………..........67
圖二十四、不同濃度的CIT 標準品與 α-CHCA 混合後添加α-環糊精：(a) 10 ppm (b) 1 ppm (c) 0.1 ppm之MALDI-TOF質譜圖……………............67
圖二十五、MALDI-TOF/MS 偵測之質譜圖：(a) 空白基質 (b) 無添加毒素真實樣品萃取的小麥..............................................72
圖二十六、真實穀物萃取MALDI-TOF/MS質譜圖：(a)含有 2 ppm CIT標準品的真實樣品(小麥) (b)含有 1 ppm CIT標準品的真實樣品(小麥) (c)含有 200 ppb CIT標準品的真實樣品(小麥)................................72
圖二十七、MALDI-TOF/MS 偵測之質譜圖：(a) 空白基質 (b) 無添加毒素真實樣品萃取的喜年來紅趜薄餅......................................73
圖二十八、真實食品萃取MALDI-TOF/MS質譜圖：(a)含有 2 ppm CIT標準品的真實樣品(紅趜薄餅) (b)含有 1 ppm CIT標準品的真實樣品(紅趜薄餅) (c)含有 200 ppb CIT標準品的真實樣品(紅趜薄餅)......................73
圖二十九、MALDI-TOF/MS 偵測之質譜圖：(a) 空白基質 (b) 無添加毒素真實樣品萃取的紅趜米.............................................74
圖三十、無矽藻土過濾的紅趜米萃取液之MALDI-TOF/MS質譜圖：含有 5 ppm CIT標準品..................................................74
圖三十一、以矽藻土過濾的紅趜米萃取液之MALDI-TOF/MS質譜圖：含有 5 ppm CIT標準品..................................................75
圖三十二、以矽藻土過濾的紅趜米萃取液之MALDI-TOF/MS質譜圖：(a)使用0.5g矽藻土(含有 5 ppm CIT標準品)。(b) 使用1g矽藻土(含有 5 ppm CIT標準品).......................................................75
圖三十三、紅麴米萃取液通過矽藻土之實驗圖片………………………..............76
圖三十四、MALDI-TOF/MS 偵測之質譜圖：(a) 空白基質 (b) 無添加毒素真實樣品萃取的紅趜膠囊...........................................77
圖三十五、以0.5g矽藻土過濾的真實食品萃取液之MALDI-TOF/MS質譜圖：(a)含有 5 ppm CIT標準品的真實樣品(紅趜膠囊) (b)含有 2 ppm CIT標準品的真實樣品(紅趜膠囊)............................................77
圖三十六、MALDI-TOF/MS 偵測之質譜圖：以0.5g矽藻土過濾並濃縮的無添加毒素真實樣品萃取的紅趜米........................................78
圖三十七、以0.5g矽藻土過濾的真實食品萃取液並濃縮之MALDI-TOF/MS質譜圖：(a)含有 5 ppm CIT標準品的真實樣品(紅趜米) (b)含有 3 ppm CIT標準品的真實樣品(紅趜米) (c)含有 1 ppm CIT標準品的真實樣品(紅趜米).......78
圖三十八、MALDI-TOF/MS 偵測之質譜圖：以0.5g矽藻土過濾並濃縮的無添加毒素真實樣品萃取的紅趜膠囊......................................79
圖三十九、以0.5g矽藻土過濾的真實食品萃取液並濃縮之MALDI-TOF/MS質譜圖：(a)含有 5 ppm CIT標準品的真實樣品(紅趜膠囊) (b)含有 3 ppm CIT標準品的真實樣品(紅趜膠囊) (c)含有 1 ppm CIT標準品的真實樣品(紅趜膠囊)..79
圖四十、紅趜代謝產物：
(1)rubropunctamin(2)citrinin(3)monascodilone(4)monascorubramin (5) monascin (6) rubropunctatin (7) ankaflavin (8) monascorubrin.............................................80
圖四十一、真實食品(紅趜薄餅)的MALDI-TOF/MS質譜圖................82
圖四十二、真實食品(紅趜米)的MALDI-TOF/MS質譜圖..................82

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