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研究生:梁蕙嘉
研究生(外文):Huey-Jie Liang
論文名稱:腐植酸對軟骨細胞毒性之研究
論文名稱(外文):Studies on the Cytotoxic Mechanisms of Humic Acid in Chondrocytes
指導教授:呂鋒洲呂鋒洲引用關係
指導教授(外文):Fung-Jou Lu
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:181
中文關鍵詞:大骨節病腐植酸軟骨細胞
外文關鍵詞:Kashin-Beck diseasehumic acidchondrocytes
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大骨節病(Kashin-Beck disease;KBD)是中國大陸盛行的一種地方性畸形骨關節病,基本的病理變化有軟骨細胞壞死(chondronecrosis)的現象。大骨節病的病因至今仍不詳,飲水中的腐植物質(humic substance)是可疑的致病因子之一。本論文將探討天然的商品腐植酸、合成腐植酸,以及酚酸單體對體外培養的兔子關節軟骨細胞之毒性效應,確立腐植酸對於軟骨細胞確實有不良影響。
我們先將美國Aldrich公司購得的商品腐植酸(AHA)以一系列有機溶劑萃取並濃縮,接著進行群落生成實驗(clonogenic assay),篩選到乙酸乙酯萃取成份(AHA-[EA])對軟骨細胞的毒性最強,於是我們進一步探討AHA-[EA]造成軟骨細胞損傷的機轉。由MTT (methylthiazol tetrazolium)檢定法實驗中發現AHA-[EA]可使軟骨細胞存活度下降;AHA-[EA]亦可造成軟骨細胞膜破損,使細胞內的乳酸脫氫(lactate dehydrogenase;LDH)釋放出來;此外,AHA-[EA]可誘導軟骨細胞發生脂質過氧化反應(lipid peroxidation),並使luminol-amplified chemiluminescence反應升高,顯示AHA-[EA]可能會引發H2O2類的活性氧物種(reactive oxygen species;ROS)之生成;而在抗氧化劑的實驗中發現catalase可保護軟骨細胞抵禦AHA-[EA]的損傷,SOD (superoxide dismutase)的添加則使軟骨細胞損傷加劇。綜合以上實驗結果,我們推測AHA-[EA]造成軟骨細胞的毒性機轉之一,可能係透過引發O2·-和H2O2等活性氧物種之生成,接著誘導軟骨細胞發生脂質過氧化反應,造成細胞膜破損,乳酸脫氫釋放出來,終而使細胞存活度下降。
由於天然腐植酸常會和一些金屬離子或其他有機物結合在一起,形成極複雜的錯合物,為了確定單純的腐植酸本身即具有毒性,我們自行合成了腐植酸。我們將化學結構已知的酚酸單體 ? 原兒茶酸(protocatechuic acid;PCA)進行氧化合成作用,形成了合成腐植酸(synthetic humic acid;SHA),接著將SHA和PCA作用至體外培養的兔子關節軟骨細胞,探討SHA和PCA對軟骨細胞的毒性作用,並分析其對軟骨細胞DNA合成、細胞週期的影響,及是否會造成轉錄因子NF-kB及AP-1之活化。
我們發現SHA和PCA皆會造成軟骨細胞存活度下降,及細胞膜破損;SHA和PCA亦會誘導軟骨細胞發生不同程度的脂質過氧化反應,及GSH depletion現象。對於O2·-和H2O2等活性氧物種之生成,兩者都沒有很明顯的誘導效應;但對於NO之生成,兩者都有抑制作用。此外,SHA和PCA皆會造成軟骨細胞內鈣離子濃度升高,使細胞內鈣離子濃度失衡;而BrdU incorporation實驗則發現SHA和PCA皆會抑制軟骨細胞合成DNA。藉由流式細胞儀(flow cytometer)的分析,發現軟骨細胞經SHA或PCA作用24小時後,皆會造成細胞的S phase減少;然僅SHA會使軟骨細胞明顯發生apoptosis現象,PCA則否。最後在EMSA (electrophoretic mobility shift assay)實驗中發現SHA有活化NF-kB及AP-1的作用。
綜合以上實驗結果,我們針對天然的商品腐植酸、合成腐植酸,及酚酸單體,以體外(in vitro)之細胞培養模式,對兔子關節軟骨細胞的傷害作用做一廣泛性的探討,確定腐植酸及酚酸單體對於軟骨細胞確實有不良影響。因此對於大骨節病的致病因子,我們認為除了中國大陸強烈懷疑的黃腐酸(fulvic acid)外,腐植酸及酚酸單體亦扮演不可忽視的角色。

Kashin-Beck disease (KBD), an endemic, chronic osteoarthritic disorder with necrosis of chondrocytes commonly occurs in China. The humic substance present in the drinking water of endemic areas has been proposed as one of the causative factors. In this study the in vitro cell culture system was used to investigate the damaging effects of naturally commercial humic acid, synthetic humic acid, and phenolic monomer on cultured rabbit articular chondrocytes.
First, the commercial Aldrich humic acid (AHA) was fractionated with a series of organic solvents including n-hexane, benzene, ethyl acetate, and methanol. Among the several fractions of AHA, the ethyl acetate fraction (AHA-[EA]) displayed the most potent inhibitory effect on the survival of chondrocytes in clonogenic assays. Cellular injury induced by AHA-[EA] was evaluated by measuring cell viability with methylthiazol tetrazolium (MTT) and by determining the release of intracellular lactate dehydrogenase (LDH). Incubation of chondrocytes with AHA-[EA] produced a concentration dependent decrease in cell viability and increase in LDH release. In addition, AHA-[EA] triggered lipid peroxidation manifested by elevated malondialdehyde (MDA) formation. In chemiluminescence assay, AHA-[EA] caused an increase of luminol-amplified chemiluminescence responses, which are considered to reflect the production of hydrogen peroxide (H2O2). Moreover, pretreating the cells with catalase significantly prevented the loss of cell viability while superoxide dismutase (SOD) enhanced the adverse effect of AHA-[EA]. Data suggest that the injury to chondrocytes induced by AHA-[EA] may be first through O2·- production, which is then converted into H2O2, thus initiating lipid peroxidation and leading to cell membrane damage as well as cell viability loss.
In order to exclude the complication of natural humic substance which is usually bound with other organic substances and inorganic ions, we prepared phenolic polymers of synthetic humic acid (SHA) from a well defined and homogeneous starting material by oxidation of phenolic compound, a protocatechuic acid (PCA). The biological effects, including cytotoxicity, DNA synthesis, cell cycle distribution, and NF-kB/AP-1 induction, of SHA and PCA on primary culture of rabbit articular chondrocytes were investigated.
We found that not only SHA but also PCA caused chondrocyte injury, as evidenced by the loss of cell viability measured with MTT assay and the increased release of intracellular LDH. Both SHA and PCA could result in lipid peroxidation and glutathione (GSH) depletion in chondrocytes. However, there were no significant effects of SHA and PCA on the production of O2·- and H2O2. Both SHA and PCA could inhibit the generation of NO. A marked increase in intracellular calcium level ([Ca2+]i) occurred after chondrocytes treated with SHA or PCA. Furthermore, an inhibitory effects of SHA and PCA on DNA synthesis detected with BrdU incorporation were observed. In flow cytometric analysis, we found that both SHA and PCA decreased the S phase of chondrocytes; but only SHA may culminate in chondrocyte apoptosis, while PCA not. Finally, SHA could induce the activations of NF-kB and AP-1 by electrophoretic mobility shift assay (EMSA).
From the above results we may confirm that both humic acid, no matter naturally occurring or synthesized, and phenolic monomer have adverse effects on chondrocytes. Data suggest that the humic acid and monomeric phenolic acid should not be ignored in exploring the causative factors of KBD in addition to fulvic acid, which is strongly suspected as one causative factor of KBD in China.

頁次
目錄 ....................................................i
縮寫表 ..................................................1
中文摘要 ................................................4
英文摘要 ................................................7

第一章 文獻背景與研究目標 ............................10
壹、大骨節病 .........................................11
貳、腐植物質 .........................................14
參、腐植物質與大骨節病 ................................16
肆、本研究室過去對腐植酸的研究 .........................16
伍、軟骨細胞 ..........................................17
陸、研究目標 ..........................................21
柒、參考文獻 ..........................................22

第二章 商品腐植酸之乙酸乙酯萃取成份對軟骨細胞的損傷..27
壹、中文摘要 ..........................................28
貳、英文摘要 ..........................................29
參、緒言 .............................................30
肆、實驗器材 .........................................32
伍、實驗方法 .........................................34
陸、實驗結果 .........................................44
柒、討論 .............................................50
捌、參考文獻 .........................................53
玖、圖表 .............................................57
圖一 .............................................58
圖二 .............................................59
表一 .............................................60
圖三 .............................................61
圖四 .............................................62
圖五 .............................................63
圖六 .............................................64
圖七 .............................................65
圖八 .............................................66
圖九(A) ..........................................67
圖九(B) ..........................................68
圖九(C) ..........................................69
表二 .............................................70
圖十 .............................................71

第三章 合成腐植酸及其單體對軟骨細胞生物活性的影響 ...72
壹、中文摘要 .........................................73
貳、英文摘要 .........................................74
參、緒言 .............................................75
肆、實驗器材 .........................................79
伍、實驗方法 .........................................82
陸、實驗結果 .........................................97
柒、討論 .............................................108
捌、參考文獻 .........................................115
玖、圖表 .............................................122
圖一 .............................................123
圖二 .............................................124
表一 .............................................125
圖三 .............................................126
圖四 .............................................127
圖五(A) ..........................................128
圖五(B) ..........................................129
圖六 .............................................130
圖七 .............................................131
圖八 .............................................132
圖九 .............................................133
圖十 .............................................134
圖十一 ...........................................135
圖十二 ...........................................136
圖十三 ...........................................137
圖十四 ...........................................138
圖十五 ...........................................139
圖十六 ...........................................140
圖十七 ...........................................141
圖十八 ...........................................142
圖十九 ...........................................143
圖二十 ...........................................144
圖二十一 .........................................145
圖二十二 .........................................146
圖二十三(A) ......................................147
圖二十三(B) ......................................148
圖二十三(C) ......................................149
圖二十四 .........................................150
圖二十五 .........................................151
圖二十六 .........................................152
圖二十七(A) ......................................153
圖二十七(B) ......................................154
圖二十七(C) ......................................155
圖二十八(A) ......................................156
圖二十八(B) ......................................157
圖二十八(C) ......................................158
圖二十九(A) ......................................159
圖二十九(B) ......................................160
圖二十九(C) ......................................161
圖三十(A) ........................................162
圖三十(B) ........................................163
圖三十(C) ........................................164
圖三十一 .........................................165
圖三十二 .........................................166
圖三十三 .........................................167

個人著作 .............................................168

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