Nuclear magnetic resonance spectroscopy and pattern recognition analysis of the biochemical processes associated with the progression of and recovery from nephrotoxic lesions in the rat induced by mercury(II) chloride and 2-bromoethanamine.
Nuclear magnetic resonance spectroscopy and pattern recognition analysis of the biochemical processes associated with the progression of and recovery from nephrotoxic lesions in the rat induced by mercury(II) chloride and 2-bromoethanamine.
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发表时间：
1992-11
影响因子：
3.6
通讯作者：
E. Holmes;F. Bonner;B. Sweatman;J. Lindon;C. Beddell;E. Rahr;J. Nicholson
中科院分区：
文献类型：
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作者：
E. Holmes;F. Bonner;B. Sweatman;J. Lindon;C. Beddell;E. Rahr;J. Nicholson
用近端肾小管毒素HgCl2和髓样毒素2-溴乙胺(BEA)诱导Fischer 344大鼠肾毒性损伤。用高分辨核磁共振氢谱观察这些毒素给药后9天以上对尿液成分的影响。诱导性毒性损伤的发生、发展和恢复也是组织病理学观察的结果，并与尿液生化紊乱有关。核磁共振在8个时间点同时测量20种内源性物质的尿液浓度，以提供每只大鼠尿液生化的时间相关的20维描述。使用主成分分析和非线性映射将每只大鼠的生化参数空间缩减到二维或三维，以便于显示和分类。对不同的数据表示方法进行了研究，在每个时间点采用动物间MAP坐标的方法，得到了一种新型的代谢轨迹图，利用该图，与HgCl2和BEA损伤相关的生化异常可能与中毒损伤的进展和恢复阶段有关。时间轨迹显示，每种毒素的路径各不相同。这些轨迹可以确定存在最大代谢差异的时间点，并提供与动物间差异相关的治疗组群体在时间上的净移动的可视化。接受这种分析的对照动物尿样显示出简单的聚集，没有代谢轨迹的证据。BEA的轨迹显示了开始中毒和从中毒中恢复的不同路线，而HgCl2的向外轨迹(开始)与向内轨迹(恢复阶段)相似。这表明，汞中毒后核磁共振可检测到的生化异常主要反映了肾单位内功能细胞的比例，而与肾髓质损伤相关的生化异常可能与功能完整性有关。已经对最负责确定轨迹的代谢物进行了检查，即肾皮质和髓质毒性彼此之间以及与对照之间的区别。这些鉴别代谢物(使用配对t检验，p<；0.001)包括氯化汞和乙酸汞的缬氨酸、牛磺酸、三甲胺N-氧化物和葡萄糖，牛磺酸的甲胺、二甲胺、乳酸和肌酸，而尚未鉴定的代谢物马尿酸、丙氨酸和2-羟基戊二酸的柠檬酸、琥珀酸、N-乙酰基共振在确定这两种毒素的生化扰动轨迹方面发挥了重要作用。
Nephrotoxic lesions were induced in Fischer 344 rats using HgCl2, a proximal tubular toxin, and 2-bromoethanamine (BEA), a medullary toxin. Biochemical effects of these toxins on urinary composition were observed by high resolution 1H NMR spectroscopy over 9 days after dosing. The onset of, progression of, and recovery from the induced toxic lesions were also followed histopathologically and related to the perturbed urinary biochemistry. Urinary concentrations of 20 endogenous substances were measured simultaneously by NMR at eight time points, to provide a time-related 20-dimensional description of the urinary biochemistry for each rat. Principal components analysis and nonlinear mapping were used to reduce the biochemical parameter spaces for each rat to two or three dimensions for display and classification purposes. An investigation of alternative data-presentation methods was made, and taking interanimal means of the map coordinates at each time point yielded a novel type of metabolic trajectory diagram with which the biochemical abnormalities associated with the HgCl2 and BEA lesions could be related to the progression and recovery phases of the toxic lesions. The time-course trajectories showed characteristically different paths for each toxin. These trajectories allowed the time points at which there were maximum metabolic differences to be determined and provided the visualization of net movements of the treatment group populations in time in relation to interanimal variation. Control animal urine samples subjected to this analysis showed simple clustering, with no evidence of metabolic trajectory. The trajectory for BEA showed different routes for onset of and recovery from toxicity, whereas for HgCl2 the outward trajectory (onset) mapped a space similar to the inward trajectory (recovery phase). This suggests that the NMR-detectable biochemical abnormalities after mercury toxicity mainly reflect the proportions of functional cells lining the nephron, whereas the biochemical abnormalities associated with renal medullary insult probably relate to functional integrity. An examination has been made for those metabolites that are most responsible for defining the trajectories, i.e., the discrimination of renal cortical and medullary toxicity from each other and from controls. These discriminatory metabolites (using paired t test, p < 0.001) included valine, taurine, trimethylamine N-oxide, and glucose for HgCl2 and acetate, methylamine, dimethylamine, lactate, and creatine for BEA, whereas citrate, succinate, N-acetyl resonances from as yet unidentified metabolites, hippurate, alanine, and 2-oxoglutarate played an important role in defining the biochemically perturbed trajectory of both toxins.(ABSTRACT TRUNCATED AT 400 WORDS)