Temporal metabonomic modeling of L-arginine-induced exocrine pancreatitis
Temporal metabonomic modeling of L-arginine-induced exocrine pancreatitis
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DOI：
10.1021/pr800407j
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Nicholson, Jeremy K.
中科院分区：
文献类型：
--
作者：
Bohus, Eszter;Coen, Muireann;Nicholson, Jeremy K.
在雄性斯普拉格 - 道利大鼠中，在7天的实验期内，使用单次腹腔注射剂量为1000和4000毫克/千克体重的L - 精氨酸（ARG），研究了其对外分泌胰腺毒性的时间相关代谢反应。使用高分辨率的氢 - 1核磁共振波谱以及补充的临床化学和组织病理学分析，对连续定时采集的尿液和血浆样本进行了分析。利用主成分分析（PCA）和潜在结构判别分析的正交投影（O - PLS - DA）来分析氢 - 1核磁共振数据，提取和识别候选生物标志物，并构建ARG给药后的代谢轨迹。低剂量的ARG几乎没有导致组织病理学损伤，并呈现出明显的可逆代谢反应轨迹。高剂量的ARG导致胰腺腺泡变性和坏死，以及具有几个不同阶段的特征性代谢轨迹图谱。初始轨迹阶段（0 - 8小时）涉及尿素循环和转氨作用的变化，表明机体对ARG分解代谢产生的过量氨进行解毒的内稳态反应。到48小时时，肠道微生物代谢产物苯乙酰甘氨酸（PAG）、4 - 甲酚 - 葡糖苷酸和4 - 甲酚 - 硫酸盐的排泄显著增加，这表明胰腺功能受损会影响肠道微生物群的活性，可能会产生一类新的胰腺损伤替代外基因组生物标志物。微生物群功能的潜在受损也可能导致继发性肝脏和胰腺毒性反应。我们在此首次展示了代谢组学研究在调查实验性胰腺炎导致的代谢紊乱方面的价值。观察到的多种全身反应表明，这种方法在评估其他动物模型或人类胰腺炎方面可能具有普遍价值。
The time-related metabolic responses to L-arginine (ARG)-induced exocrine pancreatic toxicity were investigated using single ip doses of 1000 and 4000 mg/kg body weight over a 7 day experimental period in male Sprague-Dawley rats. Sequential timed urine and plasma samples were analyzed using high resolution H-1 NMR spectroscopy together with complementary clinical chemistry and histopathology analyses. Principal components analysis (PCA) and orthogonal projection on latent structures discriminant analysis (O-PLS-DA) were utilized to analyze the H-1 NMR data and to extract and identify candidate biomarkers and to construct metabolic trajectories post ARG administration. Low doses of ARG resulted in virtually no histopathological damage and distinct reversible metabolic response trajectories. High doses of ARG caused pancreatic acinar degeneration and necrosis and characteristic metabolic trajectory profiles with several distinct phases. The initial trajectory phase (0-8 h) involved changes in the urea cycle and transamination indicating a homeostatic response to detoxify excess ammonia generated from ARG catabolism. By 48 h, there was a notable enhancement of the excretion of the gut microbial metabolites, phenylacetylglycine (PAG), 4-cresol-glucuronide and 4-cresol-sulfate, suggesting that compromised pancreatic function impacts on the activity of the gut microbiota giving potential rise to a novel class of surrogate extragenomic biomarkers of pancreatic injury. The implied compromise of microbiotal function may also contribute to secondary hepatic and pancreatic toxic responses. We show here for the first time the value of metabonomic studies in investigating metabolic disruption due to experimental pancreatitis. The variety of observed systemic responses suggests that this approach may be of general value in the assessment of other animal models or human pancreatitis.