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研究生:陳昌裕
研究生(外文):Chen Chang-Yu
論文名稱:鎳的毒性研究:脂質過氧化作用與抗氧化物效應之探討
論文名稱(外文):Nickel Toxicity: The Mechanism of Lipid Peroxidation and The Effect of Antioxidants
指導教授:林德賢林德賢引用關係
指導教授(外文):Lin Te-Hsien
學位類別:博士
校院名稱:高雄醫學院
系所名稱:醫學研究所
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:266
中文關鍵詞:氯化鎳脂質過氧化作用抗氧化物微量元素器官毒性胎盤細胞激素骨髓
外文關鍵詞:nickel chloridelipid peroxidationantioxidanttrace elementorgan toxicityplacentacytokinebone marrow
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本研究的主要目的為探討鎳所引發的器官脂質過氧化作用的機轉與微量元素的含量,來評估鎳的毒性效應。並藉由抗氧化物之影響,進一步闡明鎳之毒性作用機轉。在肝臟毒性效應的研究中發現,鎳所產生的小白鼠肝臟脂質過氧化作用與劑量和時間呈現相關性,其肝臟組織中Ni、Fe、Cu與Zn的含量,在鎳處理後,均有明顯增加。以Vit C與GSH處理後,可降低肝臟組織中因鎳所引起之脂質過氧化作用和Ni累積量。在Vit A對鎳器官毒性效應之研究結果發現,鎳可增加小白鼠肝藏、肺臟及腎臟組織的脂質過氧化作用程度,而且組織中Ni、Fe、Cu、Zn與 Ca的含量均增加。在以Vit A前處理後,肝臟之脂質過氧化作用程度、Ni和 Fe累積含量明顯增,但Cu,Zn及Ca含量有降低現象; 而在腎臟及肺臟,其脂質過氧化作用程度卻是有降低情形,Ni在腎臟及肺臟的含量亦有明顯降低,在腎臟除了Ca之外, 其Fe、Cu及Zn含量有明顯降低現象,在肺臟組織Fe、Cu、Zn及Ca含量都明顯降低。在鎳對人類胎盤毒性之體外實驗研究中發現,經鎳培養12小時內,胎盤組織之活性並未改變,但其通透性、脂質過氧化作用、以及鎳 累積含量,有明顯增加現象。在劑量效應的實驗發現,胎盤以不同 劑量Ni培養12小時後,胎盤組織之活性亦未改變,但其通透性、脂質過氧化作用、以及鎳累積含量,隨Ni培養濃度增加,有明顯增加現象。以Vit C及Zn處理後,可降低胎盤之通透性及脂質過氧化作用,但並不減少鎳在胎盤組織的累積含量。在鎳引發之脂 質過氧化作用與細胞激素含量變化的研究發現,經鎳處理後,會增加大白鼠血清中脂質過氧化作用、IL-1、TNF-a和TGF-b的含量。在鎳之劑量效應所增加的血清中MDA含量,與其所引發產生的IL-1、TNF-a和TGF-b的含量之呈現相關性。以Vit C處理後,可明顯降低鎳所引發的血清中脂質過氧化作用,細胞激素以及ALT 和AST等含量。鎳所產生的肝毒性與Ni的劑量之間呈現dose-dependent的關係,而且與血清中所增加的IL-1,TNF-a和TGF-b的含量有相關性。根據以上實驗結果,我們證實脂質過氧化作用是急性氯化鎳中毒之一種分子作用機轉,而且過渡金屬、活性含氧物質與細胞激素在鎳所引發之氧化性傷害過程中,扮演相當重要的角色。為了評估給予NiCl2對血液與骨髓(bone marrow)所產生的氧化傷害效應,因此測定血清與骨髓中脂質過氧化作用(lipid peroxidation)。NiCl2處理之老鼠其脂質過氧化作用程度,與control組比較,有隨NiCl2劑量增加而明顯增加。其血清與骨髓中Ni與Fe的濃度,亦隨NiCl2劑量增加而有顯著增加,為了探討NiCl2促進骨髓細胞脂質過氧化作用的生化機轉,對其glutathione peroxidase (GPx)的活性與α-tocopherol的含量,分別加以分析。在NiCl2給予之後,在骨髓細胞中之GPx的活性與α-tocopherol的含量,有顯著降低的現象。在骨髓細胞中之TBA-chromogen與GPx 與α-tocopherol 之間,呈現一種負相關的現象。而全血中GPx 的活性與α-tocopherol的含量,隨NiCl2劑量的增加而減少。研究結果說明, 給予高劑量NiCl2可對於骨髓細胞產生氧化性傷害作用的效應,而其骨髓中Ni 與Fe的濃度,GPx的活性和α-tocopherol 的含量,在鎳引發脂質過氧化作用的過程中,扮演重要的角色。
The purpose of this study was to investigate the effect of lipid peroxidation and concentrations of trace elements after Ni injection. To elucidate the mechanism of oxidative stress induced by Ni, the protective effects of antioxidants were also examined. Hepatic lipid peroxidation and the concentrations of Ni, Fe, Cu and Zn in the liver of mice were enhanced after injection of nickel chloride (NiCl2). Lipid peroxidation increased significantly in a dose-dependent manner. In time-course studies, both lipid peroxidation and the accumulation of Ni, Fe, Cu, and Zn in the liver showed a significantly positive time-course relationship after NiCl2 injection. Vit C and GSH significantly decreased both the levels of hepatic lipid peroxidation and the concentration of Ni in the liver, but did not decrease the accumulation of Fe, Cu, and Zn. In the study of the effects of pretrearment with Vit A on Ni toxicity. Lipid peroxidation and the concentrations of Fe, Cu, Zn and Ca in liver, kidney and lung of mice were increased after treatment with NiCl2. The extent of lipid peroxidation in Vit A+Nitreated mice was ehanced in liver, but reduced in kidney and lung. The accumulation of Ni in Vit A+Ni treated mice was increased in liver, but decreased in kidney and lung as compared to Ni- treated mice. In Vit A+Ni treated mice, as compared to Ni-treated mice, hepatic Fe was significantly increased while Cu, Zn and Ca were reduced. In the kidney of Vit A+Ni treated mice, the increase of Cu, Fe, and Zn but not Ca, was reduced. Pretreatment with Vit A reduced the increased Fe, Cu, Zn and Ca concentration in the lung caused by Ni injection. In time-course experiment, the viability of placenta explants did not show any significant change from 3 to 12 hours, whereas the permeability, lipid peroxidation and Ni accumulation were increased. In dose-response study, the viability of placenta explants did not change significantly, except for 5.0 mM Ni, but the permeability, lipid peroxidation and Ni accumulation were increased in dose-dependent manner. The lipid peroxidation in Ni-induced human term placental corresponds closely to Ni accumulation and permeability. Treatment with Vit C or Zn decreased the placental lipid peroxidation and permeability, but had no effect on decreasing the Ni accumulation. The NiCl2 administration significantly elevated the levels of malondialdehyde (MDA), IL-1, TNF-a and TGF-b in the serum of rats. The dose-effect relationship for the increase of serum MDA, corresponds closely to the increase of IL-1, TNF-a and TGF-b in serum. Treatment with Vit C significantly reduced the levels of lipid peroxidation, cytokine production and the activities of ALT and AST in the serum of the rats given NiCl2. The hepatic toxicity was increased in a dose-dependent manner after NiCl2 injection, and corresponds to the increase of serum IL-1, TNF-a and TGF-b. The experimental findings support the conclusion that lipid peroxidation constitutes a molecular mechanism of acute nickel chloride toxicity. The transition metals and reactive oxygen species and cytokine play important responsibility of oxidative damage of Ni. To evaluate whether NiCl2 treatment could affect the oxidation of serum and bone marrow cells , lipid peroxidation were determined after NiCl2 injection. Lipid peroxidation of serum and bone marrow cells increased significantly in a dose-dependent manner. The concentrations of Ni and Fe in serum and bone marrow cells were also significantly increased after NiCl2-treated. After treatment with NiCl2, the activities of glutathione peroxidase (GPx) and levels ofα-tocopherol in bone marrow cells were decreased. There was an inverse correlation between thiobarbituric acd-chromogen (TBA-chromogen) and GPx (r = -0.929,P<0.01) and α-tocopherol (r = -0.966,P<0.01) in bone marrow cells of NiCl2-treated rats. After treatment with NiCl2, the activities of GPx in blood were decreased. The oncentration of α-tocopherol in blood significant increased in a dose-dependent manner. Inclusion, nickel-induced lipid peroxidation of bone marrow cells may result from increase the amounts of Ni and Fe , as these elements are involved in the generation of hydroxyl radical by inducing the Fenton reaction, thus instigating the nickel-mediated lipid peroxidation. The inverse correlation between TBA-chromogen and GPx and α-tocopherol may imply that lipid peroxidation is associated with GPx and α-tocopherol depletion, which may contribute to the bone marrow cells injury induced by nickel.
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中文總摘要
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總目錄
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鎳對器官毒性與抗氧化物效應之結論
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