臺灣博碩士論文加值系統

摘要
雜環胺化合物 (Heterocyclic amines, HAs) 是具有不飽和雙鍵的環狀有機化合物，常發現於經熱加工之高蛋白食品中，能透過葡萄糖、胺基酸、肌酸和肌酸酐經熱作用合成，也可以直接由單一胺基酸或蛋白質經熱裂解生成。目前的研究顯示 HAs 具有致突變性與致癌性，若攝入過多對人體健康有不利的影響。在亞
洲國家，除肉類製品之外，大豆類製品的攝食量亦非常可觀，且大豆中含有豐富的豆類蛋白，對於其 HAs 之生成有必要加以探討，因此本研究探討不同加工方式(油炸、水煮及焙烤)、溫度及時間對黃豆製品中 HAs 生成的影響。在過去傳統的萃取方法較為耗時，本次實驗使用 QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) 開發出快速萃取 HAs 的條件，並利用 UPLC-MS-MS 搭配 Core shell C18 管柱，開發快速且可同步分離多種 HAs 的方法，用以檢測黃豆製品中的 HAs。結果顯示使用 10 mM 的 ammonium formate 和 acetonitrile (ACN) 的梯度溶劑系統，所檢測的 21 種 HAs 與 1 種內部標準品 (4,7,8-TriMeIQx) 可在15 分鐘內進行同步分離。研究亦針對不同萃取溶劑進行比較 (ACN, ACN+1% acetic acid, acetone, acetone+1%)，結果顯示 ACN 對豆乾及豆漿有較佳的回收率，適合用於此 QuEChERS 的條件，豆乾之平均回收率為 62~91%，豆漿之平均回收率為 64~93%。本研究方法測得豆乾基質之偵測極限 (limit of detection, LOD) 為0.008~0.15 ng/g，定量極限 (limit of quantification, LOQ) 為 0.025~0.5 ng/g；豆漿基質之偵測極限 (LOD)為 0.003~0.1 ng/mL，定量極限 (LOQ) 則為 0.01~0.5 ng/mL；豆乾基質之分析重複性及中間精密度 coefficient of variation (CV) 值分別為 4~28% 及 4~23%；而豆漿基質之分析重複性及中間精密度 CV 值分別為 1~19% 及 4~25%。顯示所開發的方法具有良好的靈敏度、準確度及精密度。豆乾樣品以油炸方式烹調產生 HAs 之含量為最高；豆乾或豆漿中 HAs 之生成均隨著加熱溫度與時間的增加而增加，此結果與過去肉類製品之文獻相似。本研究針對成年人與老年人兩族群攝食豆乾或豆漿暴露到 HAs 之健康關注程度（在此假設所有種類之 HAs 均與 PhIP 有相同毒性）進行評估。所有樣品計算出之 Margin of exposure (MOE)值均大於 10000 (屬低度風險)，但風險矩陣圖結果顯示，兩族群攝食油炸豆乾的健康風險高於水煮及焙烤的豆乾，因此較須受到關注。而豆漿以 100 °C 煮沸所產生之 HAs 較高，且保溫(60°C) 越久越容易暴露到 HAs。

Heterocyclic amines (HAs) are cyclic organic compounds with unsaturated double bonds. These compounds are often found in high-protein foods during the period of hot-processing. HAs can be synthesized by the action of glucose, amino acids, creatine, and creatinine; they can also be formed directly by thermal pyrolysis of a single amino acid or protein. HAs are mutagenic and carcinogenic, and if an
excessive intake has adverse effects on human health. In Asian countries, in addition to meat products, the intake of soybean products is also very impressive, and soybeans are rich in protein, so it is necessary to investigate the formation of HAs in soybean products. This work studied the effects of different processing methods, temperature and time on the formation of HAs in the soybean products. In the past, the traditional extraction method was time consuming. This experiment used QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) to develop conditions
for rapid extraction of HAs in soybean products; meanwhile, UPLC-MS-MS with Core shell C18 column was used to develop conditions for rapid simultaneous
separation of many HAs. The results showed that 21 HAs and one internal standard (4,7,8-TriMeIQx) were simultaneously separated in 15 minutes using a gradient solvent system composed of 10 mM ammonium formate and acetonitrile (ACN).
Regarding the comparison of various extraction solvents (ACN, ACN+1% acetic acid, acetone and acetone+1%), ACN used in QuEChERS extraction presented better HAs
recoveries from dried bean curd (62~91%) and soymilk (64~93%). For dried bean curd matrix, the limit of detection (LOD) and the limit of quantification (LOQ) were
0.008-0.15 ng/g and 0.025-0.5 ng/g, respectively; the values of coefficient of variation (CV) for the analytical repeatability and intermediate were 4~28% and 4~23%,
respectively. For soymilk matrix, LOD and LOQ were 0.003-0.5 ng/ mL and 0.01~0.5g/mL, respectively; the values of CV for the analytical repeatability and intermediate
precision were 1~19% and 4~25%, respectively. These developed methods presented good sensitivity, accuracy and precision. The content of HAs was the highest when
the dried bean curd was cooked by the mean of frying. The formation of HAs in dried bean curd and soymilk was increased with heating temperature and time, and the
result was similar to previous reports on processed meat products. This study further evaluated the degree of health concerns of adults and the elderly who were exposed to
HAs due to the consumption of soybeans or soymilk (assuming all types of HAs have the same toxicity as PhIP). The margin of exposure (MOE) values calculated for all
samples were higher than 10,000 (low risk), but the risk matrix results showed that the health risk of the two groups for HAs exposure through a consumption of the dried
bean curd was higher than that of boiled and baked bean curds; therefore, HAs exposure through consumption of the dried bean curd was more important to pay attention. HAs produced in the boiled soymilk (100 °C) was higher, and the longer the hot storage (60 ° C) time results in the higher the HAs exposure.

目錄
摘要................................................................................................................................ I
Abstract ........................................................................................................................ III
圖目錄....................................................................................................................... VIII
表目錄........................................................................................................................... X
第一章 序言.................................................................................................................. 1
第二章 文獻回顧.......................................................................................................... 4
一、雜環胺 (heterocyclic amines, HAs) .............................................................. 4
(一) 熱合成型 HAs (IQ-type) ..................................................................... 4
(二) 熱裂解型 HAs (amino-carbolines) ...................................................... 5
二、雜環胺之生物毒性...................................................................................... 11
(一) 致突變性 (Mutagenicity) ................................................................... 11
(二) 致癌性 ................................................................................................. 12
三、雜環胺之萃取純化及分析方法.................................................................. 15
(一) QuEChERS 萃取技術......................................................................... 16
(二) 雜環胺之分析 ..................................................................................... 18
四、食品中雜環胺之含量.................................................................................. 21
五、影響食品中 HAs 生成因子 ........................................................................ 23
(一) 食品種類及組成成分 ......................................................................... 24
(二) 烹調方式 ............................................................................................. 25
(三) 烹調條件 ............................................................................................. 26
(四) 副原料或調味料等添加物 ................................................................. 27
六、雜環胺攝食風險.......................................................................................... 29
(一) 雜環胺每日攝入量 ............................................................................. 29
(二) 流行病學數據 ..................................................................................... 30
(三) 風險評估與國際規範 ......................................................................... 31
一、研究目的...................................................................................................... 37
二、實驗架構...................................................................................................... 38
第四章 材料與方法.................................................................................................... 41
一、 實驗材料.............................................................................................. 41
(一) 樣品 ..................................................................................................... 41
(二) 化學試藥 ............................................................................................. 41
(三) 儀器設備 ............................................................................................. 43
二、實驗方法...................................................................................................... 45
(一) 標準溶液配置 ..................................................................................... 45
(二) UPLC 分離條件 ................................................................................... 45
(三) MS/MS 分析參數 ................................................................................ 46
(四) UPLC 動相溶液之配製 ....................................................................... 47
(五) HAs 之鑑定.......................................................................................... 47
(六) 儀器分析方法確效之評估 ................................................................. 48
(七) 萃取與純化方法 ................................................................................. 50
(八) 分析方法之確效評估 ......................................................................... 54
(九) HAs 之定量......................................................................................... 57
(十) 統計分析 ............................................................................................. 59
(十一) 風險特徵描述 (Risk characterization) .......................................... 59
第五章 結果與討論.................................................................................................... 62
一、UPLC-MS/MS 分析 22 HAs 條件建立 ...................................................... 62
(一) MS/MS 分析條件之建立 .................................................................... 62
(二) 分析管柱及溶劑梯度比較 ................................................................. 63
(三) 類黃酮對 HAs 檢測干擾之確認........................................................ 65
二、 儀器分析方法確效.................................................................................... 78
(一) 線性 (Linearity) 及範圍 (Range) ..................................................... 78
(二) 儀器偵測極限與定量極限 ................................................................. 78
(三) 準確度 (Accuracy) ............................................................................. 79
(四) 精密度 (Precision) ............................................................................. 79
三、萃取純化方法之建立.................................................................................. 80
(一) 基質測試 ............................................................................................. 80
(二) 萃取溶劑之比較 ................................................................................. 81
四、分析方法確效.............................................................................................. 82
(一) 基質效應評估 (Matrix effect) ........................................................... 82
(二) 線性 (Linearity) 及範圍 (Range) ..................................................... 83
(三) 偵測極限與定量極限 ......................................................................... 83
(四) 準確度 (Accuracy) ............................................................................. 84
(五) 精密度 (Precision) ............................................................................. 84
五、豆類樣品中 HAs 之含量 ............................................................................ 86
(一) 基質匹配檢量線 ................................................................................. 86
(二) 豆乾樣品 ............................................................................................. 86
(三) 豆漿樣品 ............................................................................................. 87
六、風險特徵描述............................................................................................ 108
(一) 暴露限值(Margin of exposure, MOE) .............................................. 109
(二) RISK21 風險矩陣圖 (Risk matrix) .................................................. 110
第六章 結論.............................................................................................................. 122
第七章 參考文獻...................................................................................................... 124
圖目錄
圖 一、雜環胺的生合成途徑 .................................................................................... 10
圖 二、DNA 鍵結物形成途徑 .................................................................................. 13
圖 三、CORE-SHELL 管柱與全多孔性管柱 .............................................................. 20
圖 四、於 UPLC-MS/MS 檢測之(A) IQ , (B) ISOIQ , (C) IQX 之斷裂碎片離子 .... 67
圖 五、INSPIRE C18 檢測 HAS 之 TIC 圖譜 .......................................................... 69
圖 六、INSPIRE C18 檢測 HAS 之 MRM 圖譜 .......................................................... 70
圖 七、ENDEAVORSIL C18 TIC 圖譜.......................................................................... 71
圖 八、ENDEAVORSIL C18 檢測 HAS 之 MRM 圖譜 ................................................ 72
圖 九、CORE-SHELL COLUMN 粒徑大小與解析度 .................................................... 73
圖 十、NAVIGATORSIL C18 TIC 圖譜 ......................................................................... 74
圖 十一、NAVIGATORSIL C18 檢測 HAS 之 MRM 圖譜 ........................................... 75
圖 十二、類黃酮 (DAIDZEIN 和 GENISTEIN) 與 MEAΑC 以 UPLC-MS/MS 檢測之比
較 ......................................................................................................................... 76
圖 十三、調整 MEAΑC 子離子對參數 (198.17→154) 之 MRM 圖譜 .................. 77
圖 十四、豆乾空白基質之 MRM 圖譜 .................................................................... 91
圖 十五、豆漿空白基質之 MRM 圖譜 .................................................................... 93
圖 十六、以不同時間進行不同方式加工之豆乾樣品 .......................................... 101
圖 十七、豆乾樣品中 HAS 之 MRM 圖譜 ............................................................. 103
圖 十八、豆漿樣品中 HAS 之 MRM 圖譜 ............................................................. 106
圖 十九、豆乾中 HAS 濃度之機率密度函數 ......................................................... 112
圖 二十、不同溫度加熱之豆漿中 HAS 濃度之機率密度函數 (A) 100 °C、(B) 80 °C
及(C) 60 °C ........................................................................................................ 113
圖 二十一、成年人(19-64 歲)與老年人( ≥ 65 歲)之豆乾攝食率 ...................... 114
圖 二十二、成年人(19-64 歲)與老年人( ≥ 65 歲)之豆漿攝食率 ......................... 114
圖 二十三、成年人(19-64 歲)與老年人( ≥ 65 歲)於豆乾所暴露之 HAS ............. 115
圖 二十四、成年人(19-64 歲)與老年人( ≥ 65 歲)於豆漿所暴露之 HAS ............. 115
圖 二十五、一般情境下 A. 成年人 B. 老年人於不同加工方式豆乾所暴露 HAS
之風險矩陣圖 ................................................................................................... 118
圖 二十六、嚴格情境下 A. 成年人 B. 老年人於不同加工方式豆乾所暴露 HAS
之風險矩陣圖 ................................................................................................... 119
圖 二十七、一般情境下 A. 成年人 B. 老年人於不同加熱溫度豆漿所暴露 HAS
之風險矩陣圖 ................................................................................................... 120
圖 二十八、嚴格情境下 A. 成年人 B. 老年人於不同加熱溫度豆漿所暴露 HAS
之風險矩陣圖 ................................................................................................... 121
表目錄
表 一、各 HAS 之結構、分子量及致突變性 ............................................................. 6
表 二、熱裂解型之 HAS 之結構與其前驅物 ............................................................. 9
表 三、HAS 於大鼠和小鼠動物試驗之致癌性 ........................................................ 13
表 四、不同國家主要 HAS 之每日膳食攝入量估計值 ........................................... 33
表 五、各文獻中 HAS 與癌症之關係 ....................................................................... 34
表 六、前列腺癌、乳腺癌及大腸癌之 MOE 推估值 ............................................. 36
表 七、UPLC 動相溶液 A、B 之梯度條件 ........................................................... 46
表 八、UPLC-MS/MS 相對離子強度規範 (%) ....................................................... 48
表 九、變異係數之規範 ............................................................................................ 50
表 十、回收率之範圍 ................................................................................................ 56
表 十一、HAS 之 MS/MS 的分析參數條件 ............................................................ 68
表 十二、儀器之 LOD、LOQ 以及線性範圍 ......................................................... 89
表 十三、儀器精密度、準確度之結果 .................................................................... 90
表 十四、豆乾以不同溶劑萃取之回收率結果 (添加 1 NG/G) ................................ 95
表 十五、豆漿以不同溶劑萃取之回收率結果 (添加 1 NG/ML) ............................. 96
表 十六、21 種雜環胺於豆乾及漿中之基質效應 ................................................... 97
表 十七、豆乾基質精密度、準確度、LOD、LOQ 及線性範圍之結果 .............. 98
表 十八、豆漿基質精密度、準確度、LOD、LOQ 及線性範圍之結果 .............. 99
表 十九、各文獻使用之分析方法、分離 HAS 之數量及分離時間 ..................... 100
表 二十、豆乾樣品中 HAS 之含量 (NG/G) ............................................................ 102
表 二十一、不同溫度加熱之豆漿樣品中 HAS 之含量 (NG/ML) ......................... 105
表 二十二、豆漿樣品保溫不同時間 HAS 之含量 (NG/ML) ................................. 105
表 二十三、一般情境下兩族群於不同加工方式豆乾暴露 HAS 之 MOE (50%) 116
表 二十四、嚴格情境下兩族群於不同加工方式豆乾暴露 HAS 之 MOE (97.5%)
........................................................................................................................... 116
表 二十五、一般情境下兩族群於不同加熱溫度豆漿暴露 HAS 之 MOE (50%) 117
表 二十六、嚴格情境下兩族群於不同加熱溫度豆漿暴露 HAS 之 MOE (97.5%)
.......................................................................................................................... 117

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