臺灣博碩士論文加值系統

Saccharomyces cerevisiae No.1所產葡萄糖耐量因子（glucose tolerance factor, GTF）可改善小鼠葡萄糖不耐症，有效降低糖尿病小鼠之血糖。本研究首先探討酵母菌GTF萃取物的組成與抗氧化活性，其次探討其基因突變安全性，以及餵食大鼠之安全性。GTF萃取物主要組成為粗蛋白（61.86%）與碳水化合物（28.55%），其蛋白質中胺基酸含量以Glutamic acid（26.8%）最多。GTF萃取物中游離胺基酸含量佔13.82 %，主要以Glutamine、Lysine、Glutamic acid、Alanine與Proline。GTF萃取物螯合亞鐵離子與清除DPPH的IC50分別為2.69 mg / mL與25.93 mg / mL，每 mg之GTF萃取物之還原亞鐵離子能力相當於3.06 □g維生素C之能力。利用Ames test進行GTF萃取物之微生物基因突變安全性測試時，濃度分別為0.025 mg / plate、0.25 mg / plate、1.25 mg / plate、2.50 mg / plate及5.00 mg / plate GTF萃取物，不論有否S9-mix添加，均不影響Salmonella typhimurium TA97、TA 98、TA 100 、TA102及TA1535五株菌株的生長。添加0.025 mg / plate GTF萃取物，對TA97、TA 98、TA 100 、TA102及TA1535所產生的自然回復（spontaneous revertants）菌數與控制組所得之比例為 0.83 - 1.25（-S9-mix）及1.00 - 1.19（+S9-mix）；添加0.25 mg / plate GTF萃取物所得之比例為1.06 - 1.33（-S9-mix）及1.06 - 1.19（+S9-mix）；添加1.25 mg / plate GTF萃取物所得之比例為1.03 - 1.46（-S9-mix）及0.94 - 1.13 （+S9-mix）；添加2.50 mg / plate GTF萃取物所得之比例為1.00 - 1.39（-S9-mix）及0.75 - 1.25（+S9-mix）；添加5.00 mg / plate GTF萃取物所得之比例為1.03 - 1.46 (-S9-mix)及1.02 - 1.35（+S9-mix），顯示 GTF萃取物不會對菌株造成微生物基因的突變。利用鼷鼠淋巴瘤細胞 L5178Y tk+/-，分別添加250 □g / mL、1000 □g / mL、2500 □g / mL及5000 □g / mL的GTF萃取物作用，relative total growth（RTG）介於95.4 - 99.1%（-S9-mix）與98.7 - 102.6%（+S9-mix）；Mutation frequency（MF）介於44.1 - 57.3% （-S9-mix）與45.4 - 54.0% （+S9-mix），皆與負控制組無顯著差異，而與正控制組有顯著差異，表示GTF萃取物並不會造成細胞毒性與細胞基因突變率增加。再以Wistar 大鼠分別餵食18 mg / kg及 180 mg / kg 劑量之 GTF萃取物 28天，其體重增加量（50.50 - 53.23 g）、飼料攝食量（560.67 - 566.91 g）、飼料利用率（0.088 - 0.093）及老鼠毛髮、眼睛、鼻子等與控制組比較均無顯著差異。餵食兩種劑量 GTF萃取物之大鼠血液白血球、紅血球、血紅素、血容積、平均血球體積、平均血球血紅素、平均血球血紅素濃度及血小板數；血漿之生化指標GOT、GPT、三酸甘油脂、總膽固醇、肌胺酸及血尿素氮；尿液之生化指標肌胺酸及尿素氮等，與控制組均無明顯差異。此外，老鼠之肝體比、腎體比、以及肝臟和腎臟之病理組織切片，與控制組亦無明顯差異。

The extract from Saccharomyces cerevisiae No.1 had been demonstrated to improve the phenomenon of impaired glucose tolerance of diabetes mouse, and was defined as glucose tolerance factor (GTF). The aim of this study was to evaluate the antioxidative activity of the GTF extract and to evaluate its safety by Ames test, mouse lymphoma tk assay, and 28-day rat feeding subacute toxicity test. The GTF extract was mainly composed by protein (61.86%), followed by carbohydrate (28.55%), and the most amino acid content in it was Glutamic acid (26.8%). The GTF extract contained 13.83% free amino acids with Glutamine, Lysine, Glutamic acid, Alanine, and Proline dominant. The total phenolic content in GTF extract was 17.20 □g gallic acid equavilent / mg. Its IC50 values for Fe2+ chelating and DPPH scavenging were 2.69 mg / mL and 25.93 mg / mL, respectively. The reducing power of this GTF extract was 3.06 mg vitamin C equavilent / mL. GTF extract at the concentration range of 0.025 - 5.00 mg / plate did not induce mutagenic effects in bacterial reverse mutation test in five Salmonella typhimurium strains (TA97, TA98, TA100, TA102, and TA1535), either with or without S9-mix activation. Similarly, at the concentration range of 250 - 5000 □g/mL GTF extract did not induce toxic and mutagenic effects in the mammalian cell gene mutation test in L5178Y tk+/- mouse lymphoma cells, either with or without S9-mix activation. Compared with control, data from a dose-dependent 28-day subacute toxicity study by feeding rats with GTF extract (18 or 180 mg/kg) demonstrated no significant changed in body weight change (50.50 - 53.23 g), food intake (560.67 - 566.91 g), food efficiency ratio (0.088 - 0.093), and ratio of liver and kidney weight to body weight. The hematological data of WBC, RBC, HGB, HCT, MCV, MCH, MCHC and PLT, the biochemical data of TG, TC, BUN, Cre, GOT and GPT, and the histopathological observation of liver and kidney concluded that the GTF extract did not cause any adverse effects in all above tested.

中文摘要………………………………………………………………II
英文摘要………………………………………………………………IV
壹、前言………………………………………………………………1
貳、文獻整理…………………………………………………………3
ㄧ、調節血糖類機能性產品與原料…………………………………3
1.酵母菌葡萄糖耐量因子……………………………………………3
2.人工合成含鉻物質…………………………………………………4
3.哺乳動物之活性低分子鉻化合物…………………………………4
4.薏仁…………………………………………………………………6
5.肉桂…………………………………………………………………6二、抗氧化物…………………………………………………………7
1.微生物來源之天然抗氧化物………………………………………7
2.蛋白質水解之抗氧化物……………………………………………8三、氧化作用與自由基………………………………………………9
1.自由基之形成………………………………………………………9
2.抗氧化物之種類……………………………………………………10
四、安全性評估之分類………………………………………………12
1.分類…………………………………………………………………12
2.毒性試驗之方法……………………………………………………13
2-1.微生物基因突變分析……………………………………………13
2-2.體外哺乳類細胞基因毒性分析…………………………………17
2-3.體外哺乳類細胞的染色體異常分析法…………………………19
2-4.動物活體基因毒性分析…………………………………………20
2-5.28天餵食毒性試驗………………………………………………21
參、實驗流程…………………………………………………………23
肆、實驗材料與方法…………………………………………………24
ㄧ、材料………………………………………………………………24
1.菌株與細胞株來源…………………………………………………24
1-1.GTF萃取物生產菌株 ……………………………………………24
1-2.Ames test 試驗菌株……………………………………………24
1-3.細胞株來源………………………………………………………24
2.動物來源……………………………………………………………24
3.培養基………………………………………………………………24
3-1.細菌培養基………………………………………………………24
3-2.Ames test用之培養基 …………………………………………25
3-3.細胞培養基………………………………………………………28
3-4.L5178Y tk+/-細胞之培養基……………………………………28
4.藥品…………………………………………………………………29
5.儀器設備……………………………………………………………30
二、實驗方法…………………………………………………………32
1.GTF萃取物之生產 …………………………………………………32
1-1.菌株保存及活化…………………………………………………32
1-2.GTF萃取物之最適生產與萃取 …………………………………32
1-3.GTF萃取物活性分析 ……………………………………………32
2.GTF萃取物之組成 …………………………………………………34
2-1.水分測定…………………………………………………………34
2-2.灰份測定…………………………………………………………34
2-3.粗蛋白分析………………………………………………………34
2-4.粗脂肪分析………………………………………………………35
2-5.總醣分析…………………………………………………………35
2-6.胺基酸組成分析…………………………………………………35
2-7.游離胺基酸分析…………………………………………………35
3.GTF萃取物之抗氧化分析 …………………………………………36
3-1.總分之定量………………………………………………………36
3-2.Trolox抗氧化當量活性測定……………………………………36
3-3.還原力測試………………………………………………………37
3-4.螯合亞鐵離子試驗………………………………………………37
3-5.清除DPPH試驗……………………………………………………38
4.GTF萃取物之安全性評估 …………………………………………38
4-1.微生物基因突變分析（Ames test）試驗 ……………………38
4-2.體外鼷鼠淋巴細胞tk分析法……………………………………41
4-3.28天餵食大鼠毒性試驗…………………………………………43
5.統計分析……………………………………………………………48
伍、結果與討論………………………………………………………49
ㄧ、組成份分析………………………………………………………49
二、GTF萃取物之抗氧化分析 ………………………………………50
三、GTF萃取物之安全性評估 ………………………………………52
1.微生物基因突變分析（Ames test 試驗）………………………52
1-1.Sal. typhimurium TA97、TA 98、TA 100、TA102及
TA1535基因型態之確認………………………………………………52
1-2.毒性試驗…………………………………………………………53
1-3.致突變試驗………………………………………………………54
2.體外鼷鼠淋巴細胞tk分析法………………………………………56
2-1.細胞毒性試驗……………………………………………………56
2-2.細胞突變試驗……………………………………………………58
3.28天餵食大鼠毒性試驗……………………………………………59
3-1.體重、攝食量、肝體比與腎體比之變化………………………59
3-2.血液組成之變化…………………………………………………60
3-3.血液生化指標之變化……………………………………………62
3-4.組織病理學之影響………………………………………………65
陸、結論………………………………………………………………67
柒、參考文獻…………………………………………………………68

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