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錄 3960
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NC090FJU00255013
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校 輔仁大學
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所 食品營養學系
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489446130
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研
究 林佳葉
生
(中)
研
究 Chia-Yeh Lin
生
(英)
論
文
高鋁對大鼠血基質氧化酵素之基因表現的影響
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稱
(中)
論
文
The Effect of High Aluminum on the Gene Expression of Heme Oxygenase in Rats
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(英)
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王果行 黃銓珍 梁善居
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位 碩士
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90
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度
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文 中文
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鍵 鋁 血紅素 血比容 血基質氧化酵素
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(中)
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鍵 aluminum hemoglobin hematocrit heme oxygenase
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(英)
在長期洗腎病患身上發現，鋁的毒性會引起小球性低血色素性貧血，這可
能與鋁干擾血基質生合成及分解酵素的活性有關，特別是誘發血基質氧化
酵素（Heme oxygenase, HO）活性。HO 是分解血基質的酵素，當活性增加
就會使血基質大量分解；現已知 HO 有三種異構物，HO-1 是熱休克蛋白會
受壓力刺激而表現，HO-2 是細胞中常規表現的型式，HO-3 的特性尚不明
瞭。鋁如何導致 HO 的活性增加，推論可能與鋁對身體具毒性傷害及壓
摘
力，而誘發 HO-1 基因大量表現有關。所以本實驗分別給予雄性 SD 大鼠腹
腔注射生理食鹽水（控制組）和氯化鋁（LD501/3，鋁 27 毫克/每公斤體
要 重），實驗期間測量其體重及貧血指標（血紅素、血比容），在第四週時
(中) 予以犧牲，分析血及肝中鋁、鐵含量、血基質合成及分解酵素的活性，並
觀察 HO-1 的基因表現情形。結果發現氯化鋁組老鼠有生長遲滯情形，在
第二週時，腹腔注射氯化鋁已能顯著降低老鼠血紅素濃度及血比容積。在
酵素活性方面，腹腔注射氯化鋁會降低 Aminolaevulinic acid dehydratase 的活
性，不過 Aminolaevulinic acid synthetase 和 HO 活性則顯著增加，此外，HO1 蛋白質生成以及 mRNA 的表現都明顯受到氯化鋁的誘發。因此，高劑量
氯化鋁會經由調節 HO-1 基因的轉錄作用而使 HO 活性大量提升，在鋁導
致的貧血上扮演重要角色。
In long-term dialysis renal patients, the aluminum（Al）toxicity could cause
microcytic, hypochromic anemia. It was thought to be associated with the
interference of Al on heme biosynthesis enzymes, especially the induction of heme
oxygenase (HO). There were three isozymes of HO, HO-1, which was also a heatshock protein, would be stimulated by stress, HO-2 was the constitutively expressed
form in body while the characteristics of HO-3 were still unknown. Therefore, the
mechanism of HO activity induction by Al might be attributed to its’ toxic effects
摘 on body and led to the HO-1 gene expression. To convince this, male SD rats were
treated with saline (control) or aluminum chloride (AlCl3; LD501/3 dose, 27 mg/kg
body weight/day) intraperitoneally, rat weights and hematological parameters
要 (hemoglobin, hematocrit) were measured during study period. After four weeks, rats
(英) were sacrificed, Al and iron (Fe) concentration in serum and liver, the activities of
heme biosynthesis enzymes and the gene expression of HO-1 were assessed. It
showed the growth of rats was retarded in AlCl3 group; moreover, the hemoglobin
concentration and hematocrit were also lower than control rats in two weeks. After
intraperitoneal injection of AlCl3, the activity of aminolaevulinic acid dehydratase
(ALAD) in rat liver decreased, but aminolaevulinic acid synthetase (ALAS) and HO
activities significantly increased. Besides, the protein and the mRNA level of HO-1
had obviously induced by AlCl3 treatment. In conclusion, high dosage of AlCl3
could elevate the activity of HO through the up-regulation of HO-1 gene
transcription which played an important role on the mechanism that mediate Al
toxicity in anemia.
論
文
目
次
第一章 前
言……………………………………………………………………….1 第二章
文獻回顧 一、 鋁………………………………………………………………26 二、 鋁中毒與透析病人的小球性貧血……………….……….….6-7 三、
鋁和貧血的關係……………………………..…..…...7-11 四、 HO 的作用與
型式………………………………..……....11-13 五、 HO-1 的生理功能與調
節………………………….….……13-16 六、 鋁對生理層次的影
響…………………………….……...16-18 七、 鋁導致貧血的可能機制和 HO
之關係……………….…...18-19 第三章 材料與方法 一、 實驗設
計………………………………………………..…...20 二、 實驗方
法………………………………………………....20-22 三、 動物犧
牲………………………………………………….……22 四、 分析樣品前處
理……………………………………………….23 五、 酵素分
析……………………………………………….…..23-28 六、 HO-1 蛋白質表
現之測定………………………………….28-31 七、 HO-1 探針（probes）之
製備…………………………….31-38 八、 HO-1 mRNA 表現之測
定…………………………………38-40 九、 貧血相關血液指標之測
定………………………….…...40-41 十、 血漿鐵與肝臟中鐵的測
定………………………...……..42 十一、 血漿與肝臟中鋁的含量測
定…………………...……….42-44 十二、 統計分
析……………………………………………………….44 第四章 結果 一、 氯
化鋁對大鼠進食及生長情形之影響………………………….45 二、 腹腔注
射氯化鋁對大鼠血液樣品及肝臟中鋁、鐵含量的影響 46 三、 腹腔注射氯
化鋁對大鼠貧血相關指標的影響……………46-47 四、 氯化鋁對肝臟中血
基質相關代謝酵素活性的影響…………….47 五、 氯化鋁對肝臟中血基質
氧化酵素第一型（Heme oxygenase type 1, HO-1）蛋白質表現的影
響…………………………………...47-48 六、 氯化鋁對肝臟中血基質氧化酵
素第一型（Heme oxygenase type 1, HO-1）mRNA 表現的影
響…………………………………..48-49 第五章 討論 一、 腹腔注射氯化鋁
對老鼠生長發育的影響………………...70-71 二、 腹腔注射氯化鋁對大鼠臟
器體重比的影響…………………….71 三、 腹腔注射氯化鋁對大鼠血液中
鋁、鐵含量的影響….….71-73 四、 腹腔注射氯化鋁對大鼠肝臟中鋁、鐵含
量的影響……..73-74 五、 腹腔注射氯化鋁對大鼠貧血相關指標的影
響…………...74-75 六、 氯化鋁對肝臟中血基質相關代謝酵素的活性之影
響…..75-76 七、 氯化鋁對 HO-1 蛋白質與 mRNA 表現的影
響……………..76-77 八、 鋁誘發 HO-1 基因表現的可能機制探
討……………………77-82 第六章 結
論……………………………………………………………………...83 參考文
獻…………………………………………………………………84-100 圖表目
錄 表一、腹腔注射的劑量換表……………………………………………….50
表二、SDS 膠體溶液之成份………………………………………………….51
表三、互補去氧核糖核酸合成方………………………………………….51 表
四、PCR 反應配方…………………………………………………………52 表
五、接合的反應液……………………………………………………….52 表
六、1.2﹪FA gel（60 ml/片）成份………………………………………...52 表
七、無焰原子吸光分析鋁之條件………………………………………….53 表
八、腹腔注射氯化鋁對大鼠體重及臟器體重比之影響………………….54 表
九、腹腔注射氯化鋁對大白鼠血漿鋁、鐵含量的影響………………….55 表
十、腹腔注射氯化鋁對大鼠貧血指標的影響…………………………….56 表
十一、腹腔注射氯化鋁對大鼠肝臟鋁、鐵含量的影響………………….57 表
十二、腹腔注射氯化鋁對老鼠肝臟中血色素代謝相關酵素活性 的影
響……………………………………………………………………….…58 表十
三、哺乳動物 HO-1 基因的誘導-反應區域……………………………59 表十
四、影響鋁吸收的因子…………………………………………….60 圖一、
RT-PCR 所選用的引子序列位置…………………………………….61 圖二、
實驗期間兩組老鼠的攝食情形之比較……………………………….62 圖三、
實驗期間兩組老鼠生長情形之比較………………………………….63 圖四、
不同蛋白質含量的電泳圖………………………………………….64 圖五、蛋
白質樣品電泳染色圖…………………………………………….64 圖六、腹腔
注射氯化鋁對大鼠肝臟 HO-1 蛋白質表現的影響……………64 圖七、以大
鼠肝臟 cDNA 為模板所夾出之 HO-1 片段的電泳圖…………65 圖八、
pGEN-T-HO-1 載體的建立…………………………………………..65 圖九、
轉化後的聚合酵素連鎖反應結果………………………………….66 圖十、由
質體上切下的 cDNA 分子大小…………….………………………66 圖十一、
RNA 電泳圖……………………………………...…………………67 圖十二、
腹腔注射氯化鋁對大鼠肝臟 HO-1 mRNA 表現情形的影響.…...67 圖十三、
HO-1 基因的誘發劑-反應區域及轉錄因子結合位置…………….68 圖十四、
肝臟細胞 HO-1 基因調節機制圖………………………………….69
參
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