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JK Nicholson, JA Timbrell and PJ Sadler
Rats were injected intraperitoneally with HgCl2 at doses of 2.5, 5, 7.5, and 10 mumol of Hg/kg. Urine was collected over a 24-hr period. At this time, plasma samples were taken and kidney damage was assessed by histological examination. Urinary gamma-glutamyltransferase levels were significantly elevated at Hg2+ doses of 7.5 and 10 mumol/kg, consistent with the detection of acute tubular necrosis by light microscopy. Resonances for a large number of low molecular weight metabolites were assigned in high resolution 1H NMR spectra of rat urine. Spectra from small volumes of urine (about 0.5 ml) were obtained in less than 5 min with no pretreatment. Significant Hg2+ dose-related decreases in the excretion of creatinine and citrate and increases of glucose, glycine, alanine, alpha-ketoglutarate, succinate, and acetate were detected. Elevated levels of lactate and creatinine in plasma of rats receiving the two highest doses were found by 1H NMR. There was a good correspondence between the histopathology, enzyme excretion, and 1H NMR urinary metabolite fingerprints in the assessment of Hg2+-induced renal damage. 1H NMR provided a sensitive measure of mercury-induced nephrotoxic lesions, and information on the molecular basis of mercury cytotoxicity was derived from the abnormal patterns of metabolite excretion. These suggested that primary metabolic effects of mercury were upon mitochondrial metabolism, in particular inhibition of certain citric acid cycle enzymes leading to decreased utilization of alpha- ketoglutarate and succinate by the renal tubular cells. The decrease in urinary citrate associated with Hg2+ dosing was attributed to intracellular, tubular acidosis with concomitant enhanced citrate reabsorption. The acidosis was assumed to arise from a combination of the inhibition of tubular carbonic anhydrase and a mild metabolic lactic acidosis due to increased activity of anaerobic pathways in the kidney. The possible extension of the 1H NMR techniques to the investigation of the nephrotoxic potential of other compounds and drugs is discussed.
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