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標題: N-乙醯半胱胺酸對於顯影劑造成之細胞毒性的治療窗口限制
Narrow Therapeutic Window of N-acetylcysteine for Radiocontrast Cytotoxicity
作者: 陳一心
Chen, Yi-Hsin
關鍵字: 顯影劑;radiocontrast;急性腎衰竭;N-乙醯半胱胺酸;acute renal failure;N-acetylcysteine
出版社: 生物醫學研究所
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Contrast is widely used in different interventional procedures and image studies but with well-recognized nephrotoxicity. Contrast-induced nephropathy(CIN) accounts for 10% causes of acute renal failure in hospital and incidence even higher as 50% in patients with cardiovascular disease, diabetes mellitus, or preexisting chronic kidney disease. Different methods such as using hydration and sodium bicarbonate had been developed to reduce the incidence of CIN. N-acetylcysteine(NAC) is used for preventing CIN on account of its antioxidant and vasodilating properties but protection effect remains controversial. We demonstrated the different dosage effect of NAC on MDCK and HK-2 cell lines representative of distal and proximal tubular cell. Cell viability of MDCK was reduced by iodixanol (non-ionic iso-osmolar contrast) more than HK-2 in WST assay. HK-2 and MDCK revealed no reduction of cell viability when treated with NAC until 10mM but HK-2 showed less cell viability than MDCK. When cotreated with NAC in the presence of contrast, no protection of NAC was observed in HK-2 but with limited protection in MDCK. Improvement of cell viability was observed in iodixanol 50mgI/mL and 100mgI/mL when cotreated with NAC 10mM and 20mM. NAC showed cytotoxic effect of MDCK in LDH assay in dosage incremental manner. Further analysis with cell cycle showed incremental of subG1 group when treated with NAC in MDCK.ATP depletion was also observed in NAC 20mM and 40mM. We also found mitochondria membrane potential loss of MDCK when treated with iodixanol 100mgI/mL. Mitochondria membrane potential loss was attenuated by NAC when treated with 10mM and 20mM in dose-response manner.The result revealed narrow protection effect of NAC. The negative effect give a hint about cautious dosage adjustment while NAC is applied to CIN prevention.

顯影劑在醫學影像檢查的地位相當重要,也廣泛的運用於各種侵入性檢查以及影像檢查。但是顯影劑有廣為所知的腎毒性,據統計在醫院內發生的急性腎衰竭病例中有百分之十是因為顯影劑所引起,而且如果患者有心血管疾病、糖尿病或是慢性腎臟病,其比例會更高,可能達到百分之五十的發生率。過去數十年來,已經發展出各式各樣的方法來預防顯影劑腎病變,例如給水補充或是以碳酸氫鈉預防,但是效果並不一致。N-乙醯半胱胺酸目前也被用來預防顯影劑腎病變,而N-乙醯半胱胺酸具有抗氧化作用以及血管擴張效果,但是臨床效果仍有部分爭議。在本研究中,我們使用不同劑量的N-乙醯半胱胺酸針對MDCK與HK-2細胞株(MDCK代表遠端腎小管細胞,HK-2代表近端腎小管細胞)看是否能降低顯影劑引起的細胞毒性。我們以iodixnaol非離子等滲透壓的顯影劑處理,並用WST分析細胞存活率,發現在不同濃度iodixnaol都是MDCK存活率較HK-2差。而N-乙醯半胱胺酸在NAC 20mM時HK-2的細胞存活率較MDCK低下。在同時給予N-乙醯半胱胺酸與iodixanol時,N-乙醯半胱胺酸對於HK-2完全沒有保護力。而N-乙醯半胱胺酸在10mM與20mM對於MDCK以50mgI/mL與100mgI/mL的iodixanol則有部分的保護效果,N-乙醯半胱胺酸對於MDCK細胞的毒性以LDH assay分析,可以得到劑量-反應圖的確認。我們還觀察到N-乙醯半胱胺酸造成MDCK細胞內ATP含量的下降。另外iodixnaol造成粒線體膜電位的喪失會經由N-乙醯半胱胺酸而減弱。所以N-乙醯半胱胺酸對於顯影劑細胞毒性的保護效果是來自於粒線體膜電位的改善。結果顯示N-乙醯半胱胺酸的保護劑量的範圍很窄。甚至高劑量N-乙醯半胱胺酸會有抑制細胞生長的表現,這個現象暗示了N-乙醯半胱胺酸用來保護顯影劑腎病變時,我們需要謹慎的調整劑量以免反而造成負面的影響。
其他識別: U0005-2308201201244700
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