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研究生:何昭德
研究生(外文):Jau-Der Ho
論文名稱:循血綠對網膜色素上皮細胞之毒性作用:從藥物副作用到一個運輸體的發現
論文名稱(外文):Cytotoxicity of Indocyanine Green on Retinal Pigment Epithelium: from Side Effect to Discovery of a Transporter
指導教授:蔡瑞芳蔡瑞芳引用關係
指導教授(外文):Ray Jui-Fang Tsai
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
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:2003
畢業學年度:91
語文別:中文
論文頁數:144
中文關鍵詞:循血綠網膜色素上皮細胞細胞毒性有機陰離子運輸體黃斑部裂孔
外文關鍵詞:indocyanine greenretinal pigment epitheliumcytotoxicityorganic anion transportermacular hole
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中文摘要
在黃斑部裂孔手術中使用循血綠(indocyanine green; ICG)(一種有機陰離子)來染色內側限薄膜(internal limiting membrane; ILM)以增加其能見度,自2000年被提出後,就一直有報告爭議此舉是否會對眼球內的細胞(尤其是視網膜色素上皮細胞細胞)造成傷害。本研究是利用體外細胞培養的方式研究循血綠對視網膜色素上皮細胞的毒性作用,發展可以減少毒性的方法,並進一步探討對視網膜色素上皮細胞吸收循血綠的機制。
在此研究工作中,首先建立循血綠毒性的體外模型,我們發現即使在低濃度下(0.01 mg/mL),長時間的暴露也可能導致視網膜色素上皮細胞的毒性,利用TUNEL染色及DNA瓊脂電泳分析,我們發現細胞表現出壞死之特徵。其次,我們建立循血綠的光動力學毒性之體外模型,發現在經循血綠暴露兩分鐘後,加以相當於手術用光源強度之光線照射40分鐘,會產生細胞毒性,而且以細胞凋亡之形式呈現(包括細胞核裂解,p53移位至細胞核)。但在兩種毒性模型中均有細胞膜上phosphatidylserine外翻之情形(一種細胞凋亡之特徵)。進一步的研究發現,若給予長期暴露於循血綠之下的視網膜色素上皮細胞葡萄糖,使其細胞內的ATP增加,將使原本走向壞死的細胞轉而走向細胞凋亡之途徑(細胞核出現裂解以及DNA發生internucleosomal cleavage),顯示ATP的含量是決定細胞死亡模式之因素。
我們的研究也顯示,除去溶液中的鈉離子,改以其他的陽離子取代時,可以有效地減少循血綠的毒性(包括長期暴露以及光動力學毒性);利用spectrophotometry,我們證實其機制在於當鈉離子不存在時視網膜色素上皮細胞對循血綠的吸收隨之減少;而這項研究結果也具備臨床上的應用價值,可以提高於玻璃體腔內使用循血綠的安全性。
在藥物動力學的探討上,我們發現視網膜色素上皮細胞對循血綠的吸收,可以分為鈉依賴及非鈉依賴兩部分,且均符合 Michaelis-Menten動力學模型,會有隨著受質濃度增加而有飽和之現象,表示其吸收是經由運輸體(transporter)進行。而其Michaelis-Menten參數分別為:Km = 0.1774 mM,Vmax = 1.032 nmol/105 cells‧min(鈉依賴部分)以及Km = 0.454 mM,Vmax = 1.545 nmol/105 cells‧min(非鈉依賴部分)。
由上述的實驗結果,我們推論視網膜色素上皮細胞上應存在有鈉依賴型的有機陰離子運輸體,將循血綠運入細胞。而在回顧文獻後,現在已被發現在視網膜色素上皮細胞上的OATP2(非鈉依賴型)以及MRP1(負責將有機陰離子排出細胞外)都無法解釋我們所觀察到之現象。藉由反轉錄─聚合酉每 鏈鎖反應(RT-PCR)以及免疫組織染色,我們發現在視網膜色素上皮細胞上存在有OAT3此一鈉依賴型有機陰離子運輸體。
總結我們的研究顯示:循血綠的長期暴露或短期暴露再施以光照後,會對視網膜色素上皮細胞產生毒性,而其死亡機制的決定因子包括了細胞內ATP的含量。去除鈉離子可以藉由減少視網膜色素上皮細胞對循血綠的吸收而減少其毒性;另一方面,我們也發現了視網膜色素上皮細胞上的一個有機陰離子運輸體-OAT3。相信這些結果將提供未來在減少循血綠藥物副作用以及探討視網膜色素上皮細胞的運輸功能上,一個新的思考方向。
ABSTRACT
Since indocyanine green (ICG; an organic anion) was firstly used to stain internal limiting membrane (ILM) during macular hole surgery in 2000, there have been controversies about its toxicity to the intraocular cells (esp. retinal pigment epithelium; RPE). The aims of this study include (1) to evaluate the cytotoxic effects of ICG on cultured human RPE, (2) to develop approaches to reduce the cytotoxicity, (3) to explore the mechanisms of ICG uptake by RPE.
Firstly, we set up an in vitro model of ICG-induced RPE cytotoxicity. We demonstrated the toxic effects of prolonged ICG exposure (3 hours) on RPE, even at a very low ICG concentration (0.01 mg/mL). Besides, the cell nuclei revealed characteristics of necrosis. The next, we established an in vitro model of ICG-induced photodynamic toxicity. After short term exposure (2 min) of 2.5 mg/mL ICG followed by 40 minutes of light illumination (4 × 104 lux; compared to the intensity of an endoillumination probe), RPE cells were apoptotic (i.e. nuclear condensation and fragmentation, p53 nuclear translocation). However, RPE in both models revealed phosphatidylserine exposure on the cell surface (a marker of apoptosis). Further study found that increasing ATP in the ICG-treated RPE cells with glucose switched the cell death pattern from necrosis to apoptosis, implying a determinant role of ATP between apoptosis and necrosis.
We also found that replacement of Na+ in the solvent by other cations significantly reduced ICG-induced RPE cytotoxicity (including those caused by prolonged exposure and photodynamic toxicity). With spectrophotometry, we demonstrated it was caused by reduced ICG uptake in the absence of Na+. This result was constructive clinically because it would enhance the safety margin of intravitreal ICG usage.
Through pharmacokinetic study, we found RPE-mediated ICG uptake was composed of two parts: Na+-dependent and Na+-independent. Both parts conformed to the Michaelis-Menten kinetics. That is, the ICG uptake was saturable with increasing substrate concentration, indicative of a transporter-mediated process. The Michaelis-Menten parameters were Km = 0.1774 mM, Vmax = 1.032 nmol/105 cells‧min (Na+-dependent part) and Km = 0.454 mM, Vmax = 1.545 nmol/105 cells‧min (Na+-independent part).
According to our results, we deduced that there was Na+-dependent organic anion transporter(s) on RPE cells which was responsible for the Na+-dependent portion of ICG uptake. The organic anion transporters found to date on RPE cells (OATP2 and MRP1) would not account for our observation, since OATP2 was Na+-independent and MRP1 mediated the extrusion of organic anions from cells, rather than uptake into cells. To address this issue, we demonstrated the existence of a Na+-dependent organic anion transporter OAT3, on human and rat RPE by RT-PCR and immunohistochemistry.
In summary, we demonstrated the ICG-induced RPE cytotoxicity, either after prolonged exposure or after short-term exposure followed by light illumination. In addition, intracellular ATP content was a determining factor for the mechanism of cell death. Removal of Na+ in the solvent reduced the cytotoxicity and photodynamic toxicity of ICG by reducing the ICG uptake by RPE. We also demonstrated the presence of an organic anion transporter (OAT3) on RPE cells. Such results may provide a new view in reducing clinical side effects of intraocular ICG use and the study of the transport function of RPE.
目錄
頁數
指導教授推薦書…………………………………………………………………………..…………
口試委員會審定書………………………………………………………………...………………
中文摘要………………………………………………………………………………………….……… viii
英文摘要………………………………………………………………………………………….……… xi
略語表(abbreviation)…………………………………………………………….………………
第一章: 緒論……………………………………………………………………………..………… 1
第二章: ICG於長期暴露下對RPE細胞之毒性…………………………… 14
第三章: 鈉離子和ICG對RPE細胞毒性之關聯………….………………. 32
第四章: ICG引起之RPE細胞的光動力學毒性
─去除鈉離子的效應………………………………………………… 49
第五章: ICG對細胞毒性及光動力學毒性之機制
─細胞凋亡VS.壞死……………………………………..…………… 62
第六章: RPE細胞對ICG uptake之藥物動力學特性………………… 85
第七章: OAT3運輸體在RPE細胞之表現……………………..……………… 99
第八章: 結語與未來展望………………………………………………………………… 115
參考文獻……………………………………………………………………………………………….… 123
附錄………………………………………………………………………………………………………….. 144
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