Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells
Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells
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DOI：
10.1016/j.freeradbiomed.2005.12.027
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发表时间：
2006-05-01
影响因子：
7.4
通讯作者：
Schafer, Freya Q.
中科院分区：
文献类型：
--
作者：
Kramarenko, Galina G.;Wilke, Werner W.;Schafer, Freya Q.
作为一种还原剂，抗坏血酸是一种抗氧化剂。然而，在某些情况下，它的还原功能可能会引发氧化级联反应，即似乎是一种“促氧化剂”。当抗坏血酸在光敏化过程中存在时，这种二分法似乎也能说明问题。抗坏血酸可以与单线态氧反应，产生过氧化氢。因此，如果在光敏化过程中存在抗坏血酸，高度可扩散的过氧化氢的堡垒可能会增强光动力作用的毒性。另一方面，抗坏血酸可以通过将高活性的单线态氧转化为活性较低的过氧化氢来降低毒性，过氧化氢可以通过谷胱甘肽和过氧化氢酶等清除过氧化氢的系统来清除。为了测试抗坏血酸对光动力治疗的影响，我们将白血病细胞(HL-60和U937)与抗坏血酸和光敏剂(维替普芬；VP)孵育，检测抗坏血酸负离子摄取、谷胱甘肽水平、膜通透性、细胞生长和毒性的变化。VP在各细胞系中的积累量相似。在我们的实验条件下，与U937细胞相比，HL-60细胞积累的抗坏血酸较少，细胞内GSH水平也较低。在没有添加抗坏血酸的情况下，HL-60细胞对VP和光处理的敏感性高于U937细胞。当细胞暴露在VP和光中时，抗坏血酸在U937细胞中起抗氧化剂的作用，而对HL-60细胞则是促氧化剂。解释这些观察结果的一个可能机制是HL-60细胞表达髓过氧化物酶活性，而U937细胞表达髓过氧化物酶活性低于检测极限。在无抗坏血酸存在的情况下，用4-氨基苯甲酸肼(4-ABAH)抑制髓过氧化物酶活性对VP对HL-60细胞的光毒性影响很小。但在VP光敏化过程中，4-ABAH可降低抗坏血酸对HL-60细胞的毒性，但不影响抗坏血酸对U937细胞的毒性。这些数据表明，抗坏血酸通过VP和LIGH增加过氧化氢的产生。这种过氧化氢会激活髓过氧化物酶，产生有毒的氧化剂。这些观察结果表明，在某些情况下，抗坏血酸可能会增强光动力作用的毒性。(C)2006 Elsevier Inc.保留所有权利。
As a reducing agent, ascorbate serves as an antioxidant. However, its reducing function can in some settings initiate an oxidation cascade, i.e., seem to be a "pro-oxidant." This dichotomy also seems to]told when ascorbate is present during photosensitization. Ascorbate can react with singlet oxygen, producing hydrogen peroxide. Thus, if ascorbate is present during photosensitization the fort-nation of highly diffusible hydrogen peroxide could enhance the toxicity of the photodynamic action. On the other hand, ascorbate could decrease toxicity by converting highly reactive singlet oxygen to less reactive hydrogen peroxide, which can be removed via peroxide-removing systems such as glutathione and catalase. To test the influence of ascorbate on photodynamic treatment we incubated leukemia cells (HL-60 and U937) with ascorbate and a photosensitizer (Verteporfin; VP) and examined ascorbic acid rnonoanion uptake, levels of glutathione, changes in membrane permeability, cell growth, and toxicity. Accumulation of VP was similar in each cell line. Under our experimental conditions, HL-60 cells were found to accumulate less ascorbate and have lower levels of intracellular GSH compared to U937 cells. Without added ascorbate, HL-60 cells were more sensitive to VP and light treatment than U937 cells. When cells were exposed to VP and light, ascorbate acted as an antioxidant in U937 cells, whereas it was a pro-oxidant for HL-60 cells. One possible mechanism to explain these observations is that HL-60 cells express myeloperoxidase activity, whereas in U937 cells it is below the detection limit. Inhibition of myeloperoxidase activity with 4-aminobenzoic acid hydrazide (4-ABAH) had minimal influence on the phototoxicity of VP in HL-60 cells in the absence of ascorbate. However, 4-ABAH decreased the toxicity of ascorbate on HL-60 cells during VP photosensitization, but had no affect on ascorbate toxicity in U937 cells. These data demonstrate that ascorbate increases hydrogen peroxide production by VP and light. This hydrogen peroxide activates myeloperoxidase, producing toxic oxidants. These observations suggest that in some settings, ascorbate may enhance the toxicity of photodynamic action. (c) 2006 Elsevier Inc. All rights reserved.