Cycling the wagons for biliverdin reductase.
Cycling the wagons for biliverdin reductase.
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骑车寻找胆绿素还原酶。
DOI：
10.1074/jbc.l109.037119
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Snyder,SolomonH
中科院分区：
文献类型：
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作者：
Sedlak,ThomasW;Snyder,SolomonH
这封信的起因是我们阅读了Maghzal等人的文章(1)。胆红素(BR)是一种主要的生理抗氧化细胞保护剂。组织水平只有纳摩尔浓度，因为高水平是神经毒性的，但BR保护免受微摩尔水平的氧化剂，因为在这个循环中，BR抗氧化作用产生的胆绿素(BV)被胆绿素还原酶(BVR)有效地转化为BR(2)。循环的其他证据包括BR非凡的抗氧化能力和增加的活性氧物种(ROS)水平、脂质氧化以及BVR耗竭组织中细胞死亡的易感性(2，3)。Maines和他的同事已经证实，BVR耗竭会加剧砷盐应激引起的细胞毒性。斯托克和他的同事们(1)证实了这些观察中的一些，但不是全部。他们没有观察到BVR耗竭细胞中氧化剂诱导的细胞死亡增加。然而，他们使用极高的过氧化氢浓度，预计将压倒生理抗氧化剂；他们在氧化剂后4-8小时检查细胞，而受BVR保护的细胞死亡阶段发生在18-24小时(2，3)。它们无法通过过度表达BVR来影响细胞ROS(参见参考文献中的图5)。1)但不包括BVR底物BV，因此可能不会产生有意义的BR水平。此外，血红素加氧酶在BR形成中是限速的，因此过度表达BVR而不添加额外的血红素加氧酶应该不会影响BR水平。他们坚持认为，氧化剂只能适度地将溴转化为BV，但他们使用的条件不佳，包括氯仿和二甲基亚砜，而且他们的一些氧化剂仍能实现25%的转化，与我们观察到的相似(2)。总而言之，斯托克研究的技术方面可以解释他们的发现与我们的发现之间的差异，但并没有对基本面提出有意义的挑战。BVR循环具有病理生理和生理重要性，在许多临床研究中，胆红素可预防心脑血管疾病(5)。
This letter was prompted by our reading of the article by Maghzal et al.(1). Bilirubin (BR) is a major physiologic antioxidant cytoprotectant. Tissue levels are only in nanomolar concentrations, because high levels are neurotoxic, yet BR protects against micromolar levels of oxidants because of a cycle wherein biliverdin (BV) generated by BR antioxidant action is efficiently reconverted by biliverdin reductase (BVR) to BR (2). Additional evidence for the cycle includes the extraordinary antioxidant potency of BR and augmented levels of reactive oxygen species (ROS), lipid oxidation, and susceptibility to cell death in BVR-depleted tissues (2, 3). Maines and colleagues (4) have confirmed that BVR depletion accentuates cytotoxicity elicited by arsenate stress. Stocker and associates (1) confirm some but not all of these observations. They fail to observe increased oxidantinduced cell death in BVR-depleted cells. However, they employ extremely high H2O2 concentrations that would be expected to overwhelm a physiologic antioxidant; they examine cells at 4–8 h post-oxidant, whereas the phase of cell death protected by BVR occurs at 18–24 h (2, 3). They fail to influence cellular ROS by overexpression of BVR (see Fig. 5 in Ref. 1) but do not include BV, the BVR substrate, so meaningful levels of BR may not be generated.Moreover, heme oxygenase is rate-limiting in BR formation so that overexpressing BVR without additional heme oxygenase should not influence BR levels. They maintain that oxidants only modestly convert BR to BV, but they use unfavorable conditions, including chloroform and dimethyl sulfoxide, and still some of their oxidants afford a 25% conversion, similar to what we observed (2). In summary, technical aspects of the Stocker study can account for discrepancies between their and our findings but do not meaningfully challenge the fundamentals. The BVR cycle has pathophysiologic as well as physiologic importance, and in numerous clinical studies bilirubin protects against cardiovascular and cerebrovascular disease (5).