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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo
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Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

机译：体内三硝酸甘油酯生物转化过程中血液和组织成分的亚硝基差异

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摘要

Nitric oxide (NO)-derived products may modify tissue constituents, forming S- and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasoclilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed "NObonomics") for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg/kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S- and N-nitrosation, and RBC 5-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitriteitrate as an index of NO/NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation ("metabolic shunting") from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the Nobonomic analysis of NO-donor metabolism and signaling.
机译：一氧化氮（NO）衍生的产品可能会修饰组织成分，形成涉及NO信号传导的S-和N-亚硝基加合物以及金属亚硝酰基。硝化血管舒张剂已被广泛使用了一个多世纪，但它们向NO的生物转化途径及其在组织中的NO供体的作用仍不清楚。通过使用代谢组学方法（称为“ NObonomics”）详细描述了体内大鼠体内基石硝化血管扩张剂三硝酸甘油酯（GTN； 0.1-100 mg / kg）的全球NO相关代谢，我们发现GTN的生物转化引发了广泛的变化遍及所有主要器官系统的组织亚硝酰化。给药后数小时仍可检测到相应的反应产物，并且血管组织不是主要的亚硝酰基化位点。广泛的心脏和肝脏修饰涉及S-和N-亚硝化，RBC 5-亚硝基硫醇的形成是有机硝酸盐代谢的敏感指标。血液中GTN衍生的氧化型NO代谢物的动力学并未反映循环或组织中的亚硝酰化模式，这使人们对血浆亚硝酸盐/硝酸盐作为NO / NO供体生物动力学指标的实用性产生怀疑。目标组织的NO代谢物的数量和类型随GTN剂量的不同而变化，表明从硫醇亚硝化到血红素亚硝基化的GTN生物转化（“代谢分流”）的主要途径发生剂量敏感性变化。我们进一步证明，GTN诱导的亚硝酰基被复杂的，组织选择性相互作用的酶催化途径调节。这些发现为深入研究GTN在药理学上相关剂量下的体内代谢提供了新的实验范式，用于NO供体代谢和信号传导的Nobonomic分析。

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