L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway
L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway
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DOI：
10.1152/ajpgi.00244.2014
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发表时间：
2014-11-15
影响因子：
4.5
通讯作者：
Ytrebo, Lars Marius
中科院分区：
文献类型：
--
作者：
Kristiansen, Rune Gangsoy;Rose, Christopher F.;Ytrebo, Lars Marius
甘氨酸是一种重要的产氨氨基酸，在急性肝衰竭（ALF）时升高。我们以前已经表明，L-鸟氨酸苯乙酸盐（OP）减弱氨的上升和颅内压的猪患有ALF，但未能证明之间的化学计量关系的变化，血浆氨水平和尿中的苯乙酰谷氨酰胺的排泄。目的是研究OP处理对苯乙酰甘氨酸途径作为替代和额外的降氨途径的影响。使用了一种经过充分验证和表征的ALF大型猪模型（门腔静脉吻合术，然后进行肝动脉结扎），该模型概括了人类ALF的主要特征。将24只雌性猪随机分为三组：1）假手术+载体，2）ALF +载体，和3）ALF + OP。与假手术组相比，ALF中动脉甘氨酸浓度显著增加（P < 0.001），与假手术组相比，从肾脏释放到体循环中的甘氨酸增加三倍。在OP处理的动物的血液和脑中，这种增加被减弱（分别为P < 0.001和P < 0.05），并且衰减与通过尿中的缀合产物苯乙酰甘氨酸排泄的甘氨酸的肾清除有关（ALF +溶媒：1，060 +/- 106 μ mol/l; ALF + OP：27，625 +/-2，670 μ mol/l; P < 0.003）。本研究的数据提供了坚实的证据，证明ALF中存在一种新的、额外的氨去除途径，涉及甘氨酸的产生和去除，这是OP的目标。
Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: 1) sham operated + vehicle, 2) ALF + vehicle, and 3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 +/- 106 mu mol/l; ALF + OP: 27,625 +/- 2,670 mu mol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.