鎘是已知的環境污染物，會造成多種疾病與癌症。穀胱甘肽(glutathione, GSH) 和金屬硫蛋白(metallothionein, MT) 是保護細胞降低鎘毒性傷害的主要因子。除此之外，第一型血紅素氧化酶(heme oxygenase-1, HO-1) 也參與了減少鎘造成的毒性傷害。我們的研究主要在探討細胞暴露於鎘的情況下，MT、GSH和HO-1表現的關聯性。中國倉鼠卵巢細胞(Chinese hamster ovary cell, CHO K1) 為MT無法表現的細胞株，我們將CHO K1細胞處理鎘，發現鎘會活化γ-glutamylcysteine synthetase (γ-GCS) 進而增加GSH的含量，大量表現金屬感應轉錄因子(metal-responsive transcription factor 1, MTF-1) 和cellular myelocytomatosis oncogene (c-Myc) 或是以siRNA降低c-Myc基因表現，γ-GCS蛋白質表現都不會受到影響。HO-1蛋白的表現會隨著鎘濃度和處理時間的增加而增加，大量表現MTF-1和c-Myc或處理 c-Myc siRNA，HO-1的表現都不受到影響。若以siRNA降低c-Myc基因表現也不會改變γ-GCS的量。但降低 MTF-1基因表現， HO-1表現卻會上升。分析c-jun NH2-terminal protein kinase (JNK) 和c-Jun的活性發現他們都會隨著鎘濃度和鎘處理的時間增加而提高，處理JNK或活性氧化物(reactive oxygen species, ROS) 抑制劑都會減少HO-1的表現以及降低JNK 和c-Jun的活性。抗鎘型中國倉鼠卵巢細胞(CdR) 具有大量表現MT的能力，與CHO K1細胞比較，在CdR細胞中要活化HO-1表現以及提高JNK和c-Jun的活性需要更高劑量的鎘，相反的以siRNA降低MTF-1基因表現，除了降低MT基因表現外，也會增加HO-1的表現。我們的結果顯示MT在降低鎘的毒性扮演著重要的角色，在缺乏MT的情況下，會活化GSH和HO-1來降低鎘所造成的毒性傷害。

Cadmium (Cd) is a known environmental pollutant that can cause a variety of diseases and cancers. Glutathione (GSH) and metallothionein (MT) are the major factors to protect cells from Cd toxicity. Besides that, heme oxygenase (HO-1) is also involved in reducing the Cd-induced damaging effect. We investigated in this study the expression of MT, GSH and HO-1 under Cd exposure. Chinese hamster ovary (CHO K1) cells, an MT quiescent cell line, were treated with Cd and GSH content was examined. GSH increased with Cd treatment, and the increase was correlated with the activation of γ-glutamylcysteine synthetase (γ-GCS) expression after Cd stimulation. Overexpression of metal-responsive transcription factor 1 (MTF-1) or cellular myelocytomatosis oncogene (c-Myc) gene did not affect the γ-GCS level in Cd-treated cells. Similarly, knockdown of c-Myc gene expression did not alter γ-GCS level. Cd treatment elevated HO-1 levels in a dose- and time-dependent manner. However, HO-1 level was not affected by overexpression of either MTF-1 or c-Myc gene, or knockdown of c-Myc mRNA. Noticeably, HO-1 increased with the knockdown of MTF-1 expression. Analysis of the activity of c-jun NH2-terminal protein kinase (JNK) and c-Jun revealed that both increased with the increments of Cd concentration. Administration inhibitor for JNK or reactive oxygen species (ROS) resulted in a decreased HO-1 level and a decreased activity of JNK and c-Jun. A higher Cd concentration was required to stimulate JNK and c-Jun activity in MT gene highly amplified CHO cells (CdR) as compared to that of parental CHO K1 cells. On the contrary, knockdown of MTF-1 expression decrease MT expression but increased HO-1 level in Cd-treated CdR cells. Our results indicate that MT plays an effective role in reducing Cd toxicity. With the defect of MT gene expression, GSH and HO-1 are produced to attenuate Cd-induced toxicological effects.

目錄
中文摘要………………………………………………………………..3
英文摘要………………………………………………………………..5
緒論……………………………………………………………………..7
材料與方法…………………………………………………………….18
結果…………………………………………………………………….26
討論…………………………………………………………………….33
參考資料……………………………………………………………….38
附圖…………………………………………………………………….47

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