臺灣博碩士論文加值系統

長期高硒（selenium）攝取會使大白鼠生長受抑制、肝臟脂肪堆積、甚至肝臟病變等中毒現象，此時需大量活性甲硫胺酸（S-adenosylmethionine, SAM）提供甲基以利硒的排除，故可能造成葉酸（folate）及膽鹼（choline）消耗量增加而造成甲基提供系統之負荷。本研究以葉酸（2.0 mg/kg diet）、膽鹼（2.0 g choline bitartrate/kg diet）在剛好滿足動物需求，並添加抗生素（1% succinylsuphathiazole）以抑制腸道菌叢製造葉酸的飲食模式下，探討在不同時期（2, 4, 6, 8週）高硒攝取（5.0 mg/kg diet）時，對於大白鼠肝臟中甲基提供系統的影響。此實驗飲食可使正常硒組動物正常生長，與餵食塊狀飼料動物相較並無差異。結果顯示，高硒組動物有生長遲緩的情形，且肝臟中葉酸含量於不同時期下顯著低於正常硒組（第8週低於正常硒組47%）；肝臟磷酸膽鹼（phosphorylcholine）含量有略低於正常硒組之趨勢；高硒組肝臟活性同半胱胺酸（S-adenosylhomocysteine, SAH）濃度顯著增加，血漿同半胱胺酸（homocysteine, Hcy）及麩胱甘（glutathione, GSH）濃度則顯著降低。高硒組之肝臟硒濃度於實驗期間皆顯著高於正常硒組5.3至21.1倍不等，以第四週累積程度最高，之後伴隨總尿液硒排除量顯著增加而逐漸降低。因此高硒代謝時為了降低肝臟硒的累積量，會增加肝臟中葉酸與膽鹼的消耗，可能造成Hcy再甲基化為甲硫胺酸（methionine, Met）的效率降低，進而使肝臟SAH濃度上升，並可能加速Hcy轉硫作用以促進GSH生成提供硒還原。故高硒代謝會提高大白鼠肝臟甲基系統的消耗，增加體內硒的排除以降低毒性。

Long-term excessive consumption of selenium (Se) by rats was shown to cause various toxic symptoms such as growth inhibition, hepatic lipid accumulation, and even necrosis to the severe degree. Metabolism of excessive Se is likely to stress up the methyl donor system due to the increasing expense of methyl donors, folate and choline for regenerating methionine. The experimental diets of this study provided rats enough of folate (2 mg/kg diet) and choline (2.0 g bitartrate/kg diet) for growth and either 0.1 mg/kg diet or 5 mg/kg diet of Se for 2 to 8 weeks to evaluate the effect of Se on hepatic methyl donor system of rats. Succinylsuphathiazole (1%, wt/wt) was added to inhibit intestinal microfloral synthesis of folate. Experimental diet with 0.1 mg Se/kg diet allowed animals growing in a similar rate as that of rats fed regular chow. Hepatic folate concentration of high Se group was significantly lowed by as much as 47% compared to normal diet. Hepatic choline (phosphorylcholine) level had the tendency to be reduced in high Se group compared to normal group. Hepatic S-adenosylhomocysteine (SAH) concentration was significantly elevated and plasma homocysteine (Hcy) and glutathione (GSH) concentrations were significantly lower in high Se group than normal group. Hepatic Se concentration of high Se group was significantly increased in all periods from 5.3 to 21.1-fold (highest level at 4th week) and gradually decreased while urinary Se excretion increased. These findings indicate that long term metabolism of excessive Se is likely to increase the demand of hepatic methylation by folate and choline, elevate hepatic SAH concentration due to reducing the remethylation of Hcy, and probably enhance the transsulfuration of Hcy to produce more GSH for excretion of hepatic Se. Therefore long term metabolism of excessive Se would enhance the expense of hepatic methyl donor system for excretion of hepatic Se for detoxification of toxic level of Se.

中文摘要………………………………………………………………………I
英文摘要………………………………………………………………………II
誌謝…………………………………………………………………………III
目錄……………………………………………………………………………IV
表目錄 ………………………………………………………..... ………VII
圖目錄 ……………………………………………………… ……………VIII
簡寫表 ……………………………………………………………………….IX
第一章 緒論 ………………………………………………….…………...1
第二章 文獻回顧 ………………………………………….……………...2
一、硒的營養必需性與毒性 ………………………………………...…...2
(一) 硒的運送、吸收與代謝… .………..………………...…………….2
(二) 硒的生化功能…………………………………..……......…………3
(三) 硒的毒性………………………………………..……..……....……6
(四) 硒的來源及建議量 …………………………………..……….....…7
二、哺乳動物的甲基化系統………………….…………………..………..7
(一) 甲基化系統簡介………………………………………….…….....…7
(二) 甲硫胺酸的代謝與重要性……………………………..…......……8
(三) 活性甲硫胺酸及活性同半胱胺酸的代謝與重要性…..…......……9
(四) 同半胱胺酸的代謝與重要性…………………………..….....…..10
(五) 甲基系統之相互調節…………………………………..….....…..12
(六) 葉酸在甲基化系統中的角色…………………………..….....…..13
(七) 膽鹼在甲基化系統中的角色…………………………..….....…..15
(八) 甲基缺乏及再補充對於甲基化系統、DNA及腫瘤生成的影響....…17
三、硒代謝與甲基系統的關係…………………………………….……...22
四、研究問題、假說與目的…………………….……………….………..23
(一) 研究問題 …………………………………………………….....….23
(二) 研究假說 ………………………………………………......……..24
(三) 研究目的…………. ……………………………………….....…..24
第三章 材料與方法 ……………………………………….………...….25
一、實驗設計 …………………………………………………………..….25
二、動物飼養環境 …………………………………………………....….27
三、飼料製備 ………………..……………………………………….…..27
四、樣品之收集與處理 ……………………………………………....….27
五、分析項目與方法 ………………………………………………....….28
(一) 肝臟及血漿中葉酸（folate）含量分析……………………......28
(二) 肝臟中膽鹼（choline）含量分析…………………………….....28
(三) 肝臟中活性甲硫胺酸（SAM）與活性高半胱胺酸（SAH）含量分析…………………………………..……............…….……….....28
(四) 肝臟及尿液中硒（selenium）濃度分析...………………….…...29
(五) 血漿中同半胱胺酸（Hcy）、麩胱甘（GSH）及半胱胺酸（Cys）濃度之分析...……………………………….……………..........……..29
(六) 肝臟中三酸甘油酯（triglycerides）含量分析…….…………...29
六、統計分析 ………………………………………………...……………30
第四章 結果 … ………………………………………….…...…………31
一、動物之生長狀況……………………………………………..…..……31
(一) 動物外觀與解剖觀察…………..………………………..….......31
(二) 體重變化…………………………………………….…....…..……31
(三) 肝重………………….. ………………………………..……..…..32
(四) 肝重與體重相對百分比...……………………………..……..…..32
二、肝臟及血漿中葉酸含量………….………..……………………….…32
(一) 肝臟中葉酸含量.………………………..……………....…………32
(二) 血漿中葉酸濃度…………………………..…………....………….33
三、肝臟中膽鹼含量……………………………………..............…33
(一) 肝臟中total choline含量……...………..……………………33
(二) 肝臟中free choline含量……….…………..………………….34
(三) 肝臟中phosphorylcholine含量……….……..……………..…34
四、肝臟中SAM與SAH含量…………………………..…...…………..….35
(一) SAM與SAH標準品圖譜….....….…………….....………………..35
(二) 肝臟中SAM、SAH含量及SAM/SAH比值…..…………........……..35
五、肝臟、紅血球、血漿及尿液硒濃度………………...……………….36
(一) 肝臟…………………………………………….…..………….…36
(二) 紅血球……………………………………………...………….…36
(三) 血漿………………………………………………...………….…37
(四) 尿液………………………………………………...…………….37
六、血漿中Hcy、GSH及Cys之濃度……………………......…………….37
(一) Hcy、GSH及Cys之標準品圖譜………………….....……………37
(二) 血漿中Hcy之濃度…………………………………....……….…38
(三) 血漿中GSH之濃度………………………………….....…………38
(四) 血漿中Cys之濃度……………………………………....……….39
七、肝臟中三酸甘油酯含量……………………………………....………39
第五章 討論 ………………………………………………………..…….51
一、動物之生長狀況…………………………..……………………..……51
(一) 動物外觀與解剖觀察…………..……...……………………....…51
(二) 體重變化…………………………………………….…………......51
(三) 肝重與體重相對百分比………………...……..……………..…..52
二、肝臟及血漿中葉酸含量……………..……………..…………………53
三、肝臟中膽鹼含量……………………………………..…………..……55
四、肝臟中SAM與SAH含量…………………………..…………….....….56
五、肝臟、紅血球、血漿及尿液硒濃度……………...………………….59
(一) 肝臟中硒濃度…..……………………..……...……………….59
(二) 紅血球中硒濃度….……………………...….…..…………….60
(三) 血漿中硒濃度……………………………………...…………….61
(四) 尿液中硒含量……………………………………...…………….61
六、血漿中Hcy、GSH及Cys之濃度…….……………..…....……………62
七、肝臟中三酸甘油酯含量………………………………....……………64
第六章 結論 …………………………………………………..………….65
參考文獻 ………………………………………………………..………….67
附錄一、肝臟及血漿中葉酸含量之分析方法……………….....……...77
附錄二、肝臟中膽鹼含量之分析方法………………………..…...…….81
附錄三、肝臟中SAM及SAH含量之分析方法………..………....………..84
附錄四、肝臟及尿液中硒含量之分析方法……………………..……..…88
附錄五、血漿中Hcy、GSH及Cys濃度之分析方法……………….…………91
附錄六、肝臟中三酸甘油酯含量之分析方法………………………………95
附錄七、血漿中血紅素之分析方法……………………….……….………97

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