The Metabolism and Toxicity of Hemin in Astrocytes
The Metabolism and Toxicity of Hemin in Astrocytes
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DOI：
10.1002/glia.21198
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发表时间：
2011-10-01
期刊：
影响因子：
6.2
通讯作者：
Robinson, Stephen R.
中科院分区：
文献类型：
--
作者：
Dang, Theresa N.;Bishop, Glenda M.;Robinson, Stephen R.
氯化高铁血红素具有细胞毒性，会导致出血性中风所致的脑损伤。为了更好地了解氯化血红素对星形胶质细胞毒性的基础，本研究对氯化血红素代谢进行了量化，并将其与细胞死亡模式进行了比较。血红素氧合酶-1(HO-1)在与氯化血红素孵育2 h后开始表达，24 h时表达最强，但在24 h内，星形胶质细胞代谢的氯化血红素比例基本保持不变，细胞内70-80%的氯化血红素保持不变。细胞在接触氯化高铁素后2小时开始出现一段时间的细胞损失期，此后逐渐加重，24小时时达到最大值，但铁络合剂1，10-菲咯啉或几种抗氧化剂(特罗克斯、N-乙酰-L-半胱氨酸和N-叔丁基-苯基硝酮)均不能减轻这种细胞损失，表明氯化血红素的毒性机制不涉及铁。虽然这些结果使得氯化血红素的毒性不太可能是由于与内源性的过氧化氢相互作用所致，但在超生理水平的过氧化氢存在下，氯化血红素的毒性增加，这种增加可以被phen缓解，这表明在某些病理条件下，从氯化血红素中释放的铁是有毒的。然而，当过氧化氢处于生理水平时，氯化血红素的毒性似乎是由其他机制引起的，这些机制可能涉及到这个模型体系中的胆红素和一氧化碳。(C)2011年Wiley-Liss，Inc.
Hemin is cytotoxic, and contributes to the brain damage that accompanies hemorrhagic stroke. In order to better understand the basis of hemin toxicity in astrocytes, the present study quantified hemin metabolism and compared it to the pattern of cell death. Heme oxygenase-1 (HO-1) expression was first evident after 2 h incubation with hemin, with maximal expression being observed by 24 h. Despite the induction of HO-1, it was found that the proportion of hemin metabolized by astrocytes remained fairly constant throughout the 24 h period, with 70-80% of intracellular hemin remaining intact. A period of cell loss began after 2 h exposure to hemin, which gradually increased in severity to reach a maximum by 24 h. This cell loss could not be attenuated by the iron chelator, 1,10-phenanthroline, or by several antioxidant compounds (Trolox, N-acetyl-L-cysteine and N-tert-butyl-aphenylnitrone), indicating that the mechanism of hemin toxicity does not involve iron. While these results make it unlikely that hemin toxicity is due to interactions with endogenous H2O2, hemin toxicity was increased in the presence of supraphysiological levels of H2O2 and this increase was ameliorated by PHEN, indicating that the iron released from hemin can be toxic under some pathological conditions. However, when H2O2 is present at physiological levels, the toxicity of hemin appears to be caused by other mechanisms that may involve bilirubin and carbon monoxide in this model system. (C) 2011 Wiley-Liss, Inc.