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Cephaloridine-induced nephrotoxicity in the Fischer 344 rat: proton NMR spectroscopic studies of urine and plasma in relation to conventional clinical chemical and histopathological assessments of nephronal damage

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Abstract

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 histologypost mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo1H NMR spectroscopic analysis of lyophilised plasma, reconstituted with2H2O 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 α-CH position. This observation suggests that1H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.

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Abbreviations

ALT:

Alanine aminotransferase

BUN:

blood urea nitrogen

CPH:

cephaloridine

DMA:

dimethylamine

DMG:

N,N-dimethyl-glycine

EDTA:

ethylenediaminetetraacetic acid

FID:

free induction decay

F344:

Fischer 344

α-glucose:

α-anomeric proton of glucose

GSH:

glutathione

HB:

3-d-hydroxybutyric acid

HSE:

Hahn spin-echo

IMP:

imipenem

i.p.:

intraperitoneal

i.v.:

intravenous

MW:

molecular weight

HgCl2 :

mercuric chloride

1H NMR:

proton nuclear magnetic resonance

PAP:

4-aminophenol

SD:

Sprague-Dawley

TMAO:

trimethylamine N-oxide

TSP:

3-trimethylsilyl-[2,2,3,3-2H4]-1-propionate

UFR:

urine flow rate

UN:

uranyl nitrate

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Authors and Affiliations

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

    Maria L. Anthony, Kevin P. R. Gartland & Jeremy K. Nicholson

  2. Department of Physical Sciences, Wellcome Research Laboratories, BR3 3BS, Beckenham, Kent, UK

    Christopher R. Beddell & John C. Lindon

Authors
  1. Maria L. Anthony
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  2. Kevin P. R. Gartland
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  3. Christopher R. Beddell
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  4. John C. Lindon
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  5. Jeremy K. Nicholson
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Anthony, M.L., Gartland, K.P.R., Beddell, C.R. et al. Cephaloridine-induced nephrotoxicity in the Fischer 344 rat: proton NMR spectroscopic studies of urine and plasma in relation to conventional clinical chemical and histopathological assessments of nephronal damage. Arch Toxicol 66, 525–537 (1992). https://doi.org/10.1007/BF01973382

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