Nicholson J K, Higham D P, Timbrell J A, Sadler P J
Department of Chemistry, Birkbeck College, University of London, UK.
Mol Pharmacol. 1989 Sep;36(3):398-404.
Quantitative changes in the urinary excretion patterns of low molecular weight compounds were followed for up to 30 days after dosing of adult Sprague-Dawley rats with single intraperitoneal injections of CdCl2 (6-24 mumol/kg), using high resolution 1H NMR multicomponent urinalysis. There was a marked reduction in the rate of urinary excretion of citrate, 2-oxoglutarate, and succinate within 4.5 hr of the administration of 24 mumol/kg Cd2+. This continued for up to 4 days after dosing in male rats and was consistent with a renal tubular acidosis, caused by inhibition of carbonic anhydrase. Histological examination of the kidneys showed no evidence of structural abnormalities at any Cd2+ dose level. Creatinine excretion was not affected by Cd2+ treatment at any dose level but hippurate excretion was significantly reduced. Severe testicular damage was noted within 24 hr of Cd2+ treatment at doses of greater than 9 mumol/kg and the degree of damage appeared to be correlated with the presence of large amounts of creatine (up to 20 mM) in the urine. Analysis of homogenates of healthy testicular material indicated the presence of high concentrations of free creatine. Cadmium-induced creatinuria appears to result from direct release of creatine from the necrotic cells of the seminiferous tubules and, hence, the measurement of creatine excretion rates may provide a useful noninvasive indicator of testicular necrosis. Because NMR is nonselective in terms of metabolite detection, this work has shed new light on the changes in urinary composition arising from Cd toxicity. As such, the technique is potentially very valuable in the search for new metabolic markers of toxicity and organ dysfunction.
给成年Sprague-Dawley大鼠单次腹腔注射CdCl2（6 - 24 μmol/kg）后，使用高分辨率1H NMR多组分尿液分析，对低分子量化合物的尿排泄模式进行了长达30天的定量变化跟踪。在给予24 μmol/kg Cd2+后4.5小时内，柠檬酸盐、2-氧代戊二酸和琥珀酸盐的尿排泄率显著降低。在雄性大鼠给药后这种情况持续长达4天，这与碳酸酐酶抑制引起的肾小管酸中毒一致。在任何Cd2+剂量水平下，肾脏的组织学检查均未发现结构异常的证据。肌酐排泄在任何剂量水平下均不受Cd2+处理的影响，但马尿酸盐排泄显著减少。在给予大于9 μmol/kg剂量的Cd2+处理后24小时内，观察到严重的睾丸损伤，损伤程度似乎与尿液中大量肌酸（高达20 mM）的存在相关。对健康睾丸组织匀浆的分析表明存在高浓度的游离肌酸。镉诱导的肌酸尿似乎是由于生精小管坏死细胞直接释放肌酸所致，因此，测量肌酸排泄率可能为睾丸坏死提供一个有用的非侵入性指标。由于NMR在代谢物检测方面是非选择性的，这项工作为Cd毒性引起的尿液成分变化提供了新的线索。因此，该技术在寻找新的毒性和器官功能障碍代谢标志物方面可能非常有价值。
