How does superoxide dismutase protect against tumor necrosis factor: A hypothesis informed by effect of superoxide on ''free'' iron
How does superoxide dismutase protect against tumor necrosis factor: A hypothesis informed by effect of superoxide on ''free'' iron
复制标题
DOI：
10.1016/s0891-5849(97)00060-9
复制
发表时间：
1997-01-01
影响因子：
7.4
通讯作者：
Fridovich, I
中科院分区：
文献类型：
--
作者：
Liochev, SI;Fridovich, I
含锰线粒体超氧化物歧化酶(MnSOD)是由肿瘤坏死因子诱导产生的，对该细胞因子的坏死效应具有保护作用。然而，肿瘤坏死因子并不增加线粒体中O-2(-)的产生。如何调和这一点？众所周知，肿瘤坏死因子通过激活磷脂酶A2(PLA(2))来增加花生四烯酸的产量。花生四烯酸在脂肪氧合酶作用下转化为相应的烷基过氧化氢。O-2(-)通过氧化[4Fe-4S]的脱水酶簇，如乌头酸酶，来增加‘’游离‘’铁。亚铁反过来与烷基过氧化氢反应，类似于Fenton反应，产生烷氧基：这可以通过自由基链式反应启动多不饱和脂肪的氧化。MnSOD通过减少O-2(-)对[4Fe-4S]团簇的攻击，从而降低游离铁，从而保护肿瘤坏死因子。聚乳酸(2)和脂氧合酶的抑制剂也应该通过减少脂肪酰基过氧化氢来保护，而且他们这样做是已知的。线粒体MnSOD很少的细胞，或者不能诱导该防御酶对肿瘤坏死因子作出反应的细胞，其细胞器中的“游离”铁的水平相对较高，从而导致脂质过氧化增强。这样的细胞将优先被这种细胞因子杀死。(C)1997年爱思唯尔科学公司。
The manganese-containing mitochondrial superoxide dismutase (MnSOD) is induced by TNF and protects against the necrotic effect of this cytokine. Yet TNF does not increase production of O-2(-) in mitochondria. How is this to be reconciled? TNF is known to increase production of arachidonate, by activation of phospholipase A2 (PLA(2)). Arachidonate will be converted to the corresponding alkyl hydroperoxide by lipoxygenase. O-2(-) increases ''free'' iron by oxidizing [4Fe-4S] clusters of dehydratases, such as aconitase. Ferrous iron In turn reacts with alkyl hydroperoxides, in an analogue of the Fenton reaction, to produce alkoxyl radicals: which can initiate the oxidation of polyunsaturated lipids by a free radical chain reaction. MnSOD protects against TNF by decreasing O-2(-) attack on [4Fe-4S] clusters and thus lowering free iron. Inhibitors of PLA(2) and of lipoxygenase should also protect by decreasing fatty acyl hydroperoxides and they are known to do so. Cells having little mitochondrial MnSOD, or cells unable to induce that defensive enzyme in response to TNF, will consequently have relatively high levers of ''free'' iron in that organelle; leading to enhanced lipid peroxidation. Such cells will be preferentially killed by this cytokine. (C) 1997 Elsevier Science Inc.