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Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat

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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.

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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-β-D-glucosaminidase

PAP:

p-aminophenol

ppm:

parts per million

TMAO:

trimethylamine N-oxide

UFR:

urine flow rate

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Authors and Affiliations

  1. Department of Chemistry, Birkbeck College, University of London, Gordon House, 29 Gordon St., WC1H OPP, London, UK

    Kevin P. R. Gartland & Jeremy K. Nicholson

  2. Department of Toxicology, Sterling Winthrop Research Centre, Willowburn Avenue, NE66 2JH, Alnwick, Northumberland, UK

    Frank W. Bonner

  3. Toxicology Unit, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, WC1N 1AX, London, UK

    John A. Timbrell

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  1. Kevin P. R. Gartland
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  2. Frank W. Bonner
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  3. John A. Timbrell
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  4. Jeremy K. Nicholson
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Gartland, K.P.R., Bonner, F.W., Timbrell, J.A. et al. Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat. Arch Toxicol 63, 97–106 (1989). https://doi.org/10.1007/BF00316430

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  • DOI: https://doi.org/10.1007/BF00316430

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