Anthony M L, Gartland K P, Beddell C R, Lindon J C, Nicholson J K
Department of Chemistry, Birkbeck College, University of London, UK.
Arch Toxicol. 1992;66(8):525-37. doi: 10.1007/BF01973382.
The acute toxicological effects of the nephrotoxic antibiotic cephaloridine (CPH, 0-1500 mg/kg) in male Fischer 344 (F344) rats, have been investigated over 48 h using clinical chemistry, histopathology and proton nuclear magnetic resonance (1H NMR) spectroscopy of urine and plasma. High field (400 and 600 MHz)1H NMR urinalysis revealed increased excretion of lactic acid, acetoacetate, alanine, valine, lysine, glutamine and glutamate and a severe, time-dependent glycosuria. A major change observed in urine of CPH-treated animals was the dose-dependent increase in HB which may relate to altered energy metabolism. CPH also caused dose-dependent decreases in the urinary excretion of hippurate, allantoin and protein (conventional assay). This abnormal metabolic profile is consistent with a functional defect in the S1/S2 regions of the proximal tubule, and was confirmed by histology post mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo 1H NMR spectroscopic analysis of lyophilised plasma, reconstituted with 2H2O revealed an abnormal phase modulation of the methyl signal from free alanine and it is postulated that this is due to the release of transaminases from damaged tissue which via a reversible conversion to pyruvate, cause variable deuteration of alanine at the alpha-CH position. This observation suggests that 1H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.
利用临床化学、组织病理学以及尿液和血浆的质子核磁共振（1H NMR）光谱技术，对肾毒性抗生素头孢噻啶（CPH，0 - 1500毫克/千克）在雄性Fischer 344（F344）大鼠中48小时内的急性毒理学效应进行了研究。高场（400和600兆赫）1H NMR尿液分析显示，乳酸、乙酰乙酸、丙氨酸、缬氨酸、赖氨酸、谷氨酰胺和谷氨酸的排泄增加，且出现严重的、时间依赖性的糖尿。在接受CPH治疗的动物尿液中观察到的一个主要变化是HB呈剂量依赖性增加，这可能与能量代谢改变有关。CPH还导致马尿酸盐、尿囊素和蛋白质（传统检测方法）的尿排泄量呈剂量依赖性降低。这种异常的代谢谱与近端小管S1/S2区域的功能缺陷一致，并在死后组织学检查中得到证实。观察到的功能变化包括血尿素氮（BUN）升高、尿流率（UFR）升高以及尿渗透压呈剂量相关降低。用2H2O复溶的冻干血浆的自旋回波1H NMR光谱分析显示，游离丙氨酸甲基信号出现异常相位调制，据推测这是由于受损组织释放转氨酶，通过可逆转化为丙酮酸，导致丙氨酸在α-CH位置发生可变氘化。这一观察结果表明，1H NMR光谱模式也取决于血浆转氨酶水平，这可能为组织损伤提供一种新的指标。
