Durham Tom, Zander David, Stomeo Niccolò, Minnion Magdalena, Hogarth Graeme, Feelisch Martin, Singer Mervyn, Dyson Alex
Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK.
Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital and Institute for Life Sciences, University of Southampton, Southampton, UK.
Br J Pharmacol. 2020 Feb;177(4):745-756. doi: 10.1111/bph.14670. Epub 2019 May 23.
A clinical need exists for targeted, safe, and effective sulfide donors. We recently reported that ammonium tetrathiomolybdate (ATTM) belongs to a new class of sulfide-releasing drugs. Here, we investigated the cellular uptake mechanisms of this drug class compared to sodium hydrosulfide (NaHS) and the effects of a thiometallate tungsten congener of ATTM, ammonium tetrathiotungstate (ATTT).
In vitro H S release was determined by headspace gas sampling of vials containing dissolved thiometallates. Thiometallate and NaHS bioactivity was assessed by spectrophotometry-derived sulfhaemoglobin formation. Cellular uptake dependence on the anion exchange protein (AE)-1 was investigated in human red blood cells. ATTM/glutathione interactions were assessed by LC-MS/MS. Rodent pharmacokinetic and pharmacodynamic studies focused on haemodynamics and inhibition of aerobic respiration.
ATTM and ATTT both exhibit temperature-, pH-, and thiol-dependence of sulfide release. ATTM/glutathione interactions revealed the generation of inorganic and organic persulfides and polysulfides. ATTM showed greater ex vivo and in vivo bioactivity over ATTT, notwithstanding similar pharmacokinetic profiles. Cellular uptake mechanisms of the two drug classes are distinct; thiometallates show dependence on AE-1, while hydrosulfide itself was unaffected by inhibition of this pathway.
The cellular uptake of thiometallates relies upon a plasma membrane ion channel. This advances our pharmacological knowledge of this drug class, and further supports their utility as cell-targeted sulfide donor therapies. Our results indicate that, as a more stable form, ATTT is better suited as a copper chelator. ATTM, a superior sulfide donor, may additionally participate in intracellular redox recycling.
This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
临床上需要靶向性、安全且有效的硫化物供体。我们最近报道，四硫代钼酸铵（ATTM）属于一类新型的硫化物释放药物。在此，我们研究了与氢硫化钠（NaHS）相比这类药物的细胞摄取机制，以及ATTM的硫金属酸盐钨同类物四硫代钨酸铵（ATTT）的作用。
通过对含有溶解硫金属酸盐的小瓶进行顶空气体采样来测定体外硫化氢释放。通过分光光度法测定硫血红蛋白形成来评估硫金属酸盐和NaHS的生物活性。在人红细胞中研究细胞摄取对阴离子交换蛋白（AE）-1的依赖性。通过液相色谱-串联质谱法评估ATTM/谷胱甘肽相互作用。啮齿动物的药代动力学和药效学研究集中于血流动力学和对有氧呼吸的抑制。
ATTM和ATTT均表现出硫化物释放对温度、pH和硫醇的依赖性。ATTM/谷胱甘肽相互作用揭示了无机和有机过硫化物及多硫化物的生成。尽管药代动力学特征相似，但ATTM在体外和体内的生物活性均高于ATTT。这两类药物的细胞摄取机制不同；硫金属酸盐显示出对AE-1的依赖性，而硫化氢本身不受该途径抑制的影响。
硫金属酸盐的细胞摄取依赖于质膜离子通道。这推进了我们对这类药物的药理学认识，并进一步支持了它们作为细胞靶向硫化物供体疗法的效用。我们的结果表明，作为一种更稳定的形式，ATTT更适合作为铜螯合剂。ATTM作为一种更优的硫化物供体，可能还参与细胞内氧化还原循环。
本文是生物学与医学中硫化氢主题部分的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc。
