Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health
Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health
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DOI：
10.3109/10715762.2014.1003372
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发表时间：
2015-06-01
影响因子：
3.3
通讯作者：
Day, B. J.
中科院分区：
文献类型：
--
作者：
Chandler, J. D.;Day, B. J.
硫氰酸盐 (SCN-) 是哺乳动物生物学中普遍存在的分子，在细胞外液中浓度高达 mM。 H2O2 对 SCN- 进行双电子氧化，产生次硫氰酸 (HOSCN)，这是一种有效的抗菌物质。该反应由脊索动物过氧化物酶（例如髓过氧化物酶和乳过氧化物酶）催化，发生在人类分泌粘膜中，包括口腔、气道和消化道，并作为先天免疫的一部分调节常驻和短暂菌群。 SCN-水平的增加限制了一系列2电子氧化剂（H2O2、次卤酸和卤代胺）的浓度，有利于HOSCN的形成，通过替代可修复的硫醇和硒醇氧化而不是生物分子降解来改变对宿主组织的氧化影响。这种炎症氧化的微调与维持宿主防御和减少感染期间宿主损伤有关，部分原因是哺乳动物与其病原体之间硫氧还蛋白还原酶系统的系统发育差异。这些差异可以通过 SCN- 的药理用途来利用。最近的临床前研究已经确定了 SCN- 在肺和心血管动物模型中的抗微生物和抗炎作用，这对治疗感染性肺病和动脉粥样硬化具有重要意义。值得进一步研究以扩展这些发现并确定 SCN- 可能有用的其他疾病。高口服生物利用度和对 SCN- 对促炎反应子集的生化作用的了解的增加表明了其临床实用性。
Thiocyanate (SCN-) is a ubiquitous molecule in mammalian biology, reaching up to mM concentrations in extracellular fluids. Two-electron oxidation of SCN- by H2O2 produces hypothiocyanous acid (HOSCN), a potent anti-microbial species. This reaction is catalyzed by chordate peroxidases (e.g., myeloperoxidase and lactoperoxidase), occurring in human secretory mucosa, including the oral cavity, airway, and alimentary tract, and regulates resident and transient flora as part of innate immunity. Increasing SCN- levels limits the concentrations of a family of 2-electron oxidants (H2O2, hypohalous acids, and haloamines) in favor of HOSCN formation, altering the oxidative impact on host tissue by substitution of repairable thiol and selenol oxidations instead of biomolecule degradation. This fine-tuning of inflammatory oxidation paradoxically associates with maintained host defense and decreased host injury during infections, due in part to phylogenetic differences in the thioredoxin reductase system between mammals and their pathogens. These differences could be exploited by pharmacologic use of SCN-. Recent preclinical studies have identified anti-microbial and anti-inflammatory effects of SCN- in pulmonary and cardiovascular animal models, with implications for treatment of infectious lung disease and atherogenesis. Further research is merited to expand on these findings and identify other diseases where SCN- may be of use. High oral bioavailability and an increased knowledge of the biochemical effects of SCN- on a subset of pro-inflammatory reactions suggest clinical utility.