Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat |
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Authors: | Kevin P R Gartland Frank W Bonner John A Timbrell Jeremy K Nicholson |
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Institution: | (1) Department of Chemistry, Birkbeck College, University of London, Gordon House, 29 Gordon St., WC1H OPP London, UK;(2) Department of Toxicology, Sterling Winthrop Research Centre, Willowburn Avenue, NE66 2JH Alnwick, Northumberland, UK;(3) Toxicology Unit, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, WC1N 1AX London, UK |
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Abstract: | The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and 1H-NMR spectroscopic methods. Dosing PAP (25–100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. 1H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, 1H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by 1H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by 1H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. 1H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.Abbreviations ALP
alkaline phosphatase
- APAP
paracetamol
- BUN
blood urea nitrogen
- GFR
glomerular filtration rate
- GOT
glutamate oxaloacetate transaminase
- LAP
leucine aminopeptidase
- LDH
lactate dehydrogenase
- MW
molecular weight
- NAG
N-acetyl--D-glucosaminidase
- PAP
p-aminophenol
- ppm
parts per million
- TMAO
trimethylamine N-oxide
- UFR
urine flow rate |
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Keywords: | Aminoaciduria Citric acid Glycosuria 1H-NMR Lactic acid Nephrotoxicity p-Aminophenol Urinalysis Urinary enzymes |
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