Human pharmacology of hydrogen sulfide, putative gaseous mediator.
Human pharmacology of hydrogen sulfide, putative gaseous mediator.
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硫化氢（假定的气体介质）的人体药理学。
DOI：
10.1111/j.1365-2125.2010.03690.x
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发表时间：
2010
影响因子：
3.4
通讯作者：
James M. Ritter
中科院分区：
文献类型：
--
作者：
James M. Ritter
一氧化氮(NO)是第一个被确立为生物介体的低分子无机气体，以前只被视为一种有毒污染物。它被一氧化碳(CO)--作为废气可能致命的废气--与从小就被视为家用供暖危害的一代人的思想联系在一起，但也通过可诱导的和/或构成形式的血红素加氧酶在哺乳动物组织中与胆绿素一起形成，并随后作为信号分子参与其中，不仅在中枢神经系统(尤其是嗅觉通路)和心血管系统中，而且在呼吸、胃肠、内分泌和生殖功能中[1]。一代又一代的小学生都知道硫化氢(硫化氢)是一种生物学背景--它是臭鸡蛋气味的来源--但即便如此，21世纪初提出的硫化氢也是一种气体介质的提议受到了一些怀疑。此前，人们已经研究了硫化氢的毒理学[3]，并确定了对包括单胺氧化酶和碳酸酐酶在内的酶的作用，但最近的研究也表明，丰富多样的药理作用与生理条件下作为信号分子的功能一致。在一系列实验疾病模型的病理生理学中，它也被认为既是有害的，也是一种保护因素[4]，其治疗潜力引起了人们的评论[5]。这三种气体介体之间有惊人的相似之处，也有不同之处，这是它们之间复杂且尚未完全理解的功能相互作用的基础。这三种分子都是高度易扩散的不稳定分子，可迅速从体内排除：尿液中的NO以亚硝酸盐和硝酸盐的形式存在，以及呼出的空气中的NO；呼出的空气中的CO；尿液中的硫代硫酸盐、亚硫酸盐和硫酸盐(图1)以及呼气中的(出现，见下图)。这三种物质都与血红蛋白反应，从血红素和珠蛋白与NO的不同反应中生成高铁血红蛋白或亚硝基血红蛋白(分别是非活性和活性代谢物)；从一氧化碳或硫化氢中生成羧基血红蛋白或硫化血红蛋白。这三种物质都是通过对细胞色素c氧化酶的作用来影响细胞能量学的。这三种药物都有血管扩张作用，而且都在低浓度下具有抗炎和细胞保护作用，而不是在较高浓度下引起细胞损伤--这与Paracelsus的格言一致，即药物和毒药之间的区别完全取决于剂量。
Nitric oxide (NO), the first low molecular weight inorganic gas to be established as a biological mediator, had previously been regarded merely as a toxic pollutant. It was joined, similarly implausibly to the minds of a generation brought up with the hazards of coal gas as domestic heating, by carbon monoxide (CO) – potentially lethal as an exhaust gas, but also formed in mammalian tissues together with biliverdin by inducible and/ or constitutive forms of haem oxygenase, and implicated subsequently as a signalling molecule, not only in the central nervous system (especially olfactory pathways) and cardiovascular system but also in respiratory, gastrointestinal, endocrine and reproductive functions [1]. Hydrogen sulfide (H2S) was known to generations of schoolboys in one biological context – as the source of the odour of rotten eggs – but even so, the proposal in the early 2000s [2] that it too is a gaseous mediator was met with some scepticism.The toxicology of H2S had previously been studied [3], and actions on enzymes including monoamine oxidase and carbonic anhydrase identified, but more recent work has also shown a rich and diverse pharmacology consistent with functions as a signalling molecule under physiological conditions. It has also been implicated both as a harmful and also as a protective factor in the pathophysiology of a range of experimental models of disease [4], and its therapeutic potential has attracted comment [5]. There are striking similarities between these three gaseous mediators, as well as contrasts, that underlie complex and imperfectly understood functional interactions between them. All three are highly diffusible labile molecules that are rapidly eliminated from the body: NO as nitrite and nitrate in urine as well as NO in exhaled air; CO in exhaled air; H2S as thiosulfate, sulfite and sulfate in urine (Figure 1) as well as (it emerges, see below) in exhaled breath. All three react with haemoglobin, yielding methaemoglobin or nitrosylhaemoglobin (respectively inactive and active metabolites) from distinct reactions of haem and of globin with NO; carboxyhaemoglobin or sulfhaemoglobin from CO or H2S. All three affect cellular energetics via actions on cytochrome c oxidase. All three have vasodilator effects, and all have anti-inflammatory and cytoprotective effects at low concentrations in contrast to causing cellular injury at higher concentrations – consistent with Paracelsus’s aphorism that the distinction between drugs and poisons is determined exclusively by the dose.