Hypothiocyanous acid is a more potent inducer of apoptosis and protein thiol depletion in murine macrophage cells than hypochlorous acid or hypobromous acid
Hypothiocyanous acid is a more potent inducer of apoptosis and protein thiol depletion in murine macrophage cells than hypochlorous acid or hypobromous acid
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DOI：
10.1042/bj20080468
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发表时间：
2008-09-01
影响因子：
4.1
通讯作者：
Hawkins, Clare L.
中科院分区：
文献类型：
--
作者：
Lloyd, Mitchell M.;van Reykt, David M.;Hawkins, Clare L.
次卤酸由活化的白细胞通过形成H2 O2和释放过氧化物酶（骨髓过氧化物酶和嗜酸性粒细胞过氧化物酶）产生。这些物质是重要的杀菌剂，但HOCl（次氯酸）和HOBr（次溴酸）也与许多炎性疾病的组织损伤有关。HOSCN（次硫氰酸;氰基次磺酸）是比HOCl或HOBr更温和、更硫醇特异性的氧化剂，因此由于选择性靶向蛋白质上的关键硫醇残基，因此可能是细胞功能障碍的更有效诱导剂。在本研究中，HOCl和HOBr显示与巨噬细胞（J774A.1）快速反应，导致与HOSCN相比更大程度的细胞溶解。然而，HOSCN比HOCl或HOBr以更高的功效和更低的浓度诱导细胞凋亡和坏死。细胞凋亡与细胞质释放增加有关，但与半胱天冬酶活性无关。类似地，在半胱天冬酶抑制剂存在下处理细胞时观察到细胞凋亡，表明其由半胱天冬酶非依赖性途径介导。HOSCN比HOCl或HOBr更有效地氧化蛋白质硫醇。HOSCN在诱导细胞凋亡中的更大功效归因于对关键线粒体膜蛋白巯基的选择性损伤，导致渗透性增加和随后细胞色素c渗漏到胞质溶胶中。这种由HOSCN引起的损伤的诱导在吸烟引起的SCN-（硫氰酸根离子）水平升高的人中可能是至关重要的，并且在与这种生物损伤相关的病理学中起作用。
Hypohalous acids are generated by activated leucocytes, via the formation of H2O2 and the release of peroxidase enzymes (myelo-peroxidase and eosinophil peroxidase). These species are important bactericidal agents, but HOCl (hypochlorous acid) and HOBr (hypobromous acid) have also been implicated in tissue damage in a number of inflammatory diseases. HOSCN (hypothiocyanous acid; cyanosulfenic acid) is a milder, more thiol-specific, oxidant than HOCl or HOBr and as such may be a more potent inducer of cellular dysfuntion due to selective targeting of critical thiol residues on proteins. In the present study, HOCl and HOBr are shown to react rapidly with macrophage (J774A.1) cells, resulting in a greater extent of cell lysis compared with HOSCN. However, HOSCN induces apoptosis and necrosis with greater efficacy, and at lower concentrations, than HOCl or HOBr. Apoptosis occurs in conjunction with an increased release of cytosol, but no associated increase in caspase activity. Similarly, apoptosis is observed on treating the cells in the presence of a caspase inhibitor, suggesting that it is mediated by a caspase-independent pathway. HOSCN oxidized protein thiols more efficiently than either HOCl or HOBr. The greater efficacy of HOSCN in inducing apoptosis is attributed to selective damage to critical mitochondrial membrane protein thiol groups, resulting in increased permeability and subsequent leakage of cytochrome c into the cytosol. This induction of damage by HOSCN may be of critical importance in people with elevated levels of SCN-(thiocyanate ions) arising from cigarette smoking, and plays a role in the pathologies associated with this biological insult.