Studies on the comparative toxicity of S-(1,2-dichlorovinyl)-L-cysteine,S-(1,2-dichlorovinyl)-L-homocysteine and 1,1,2-trichloro-3,3,3-trifluoro-1-propene in the Fischer 344 rat |
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Authors: | Maria L Anthony Christopher R Beddell John C Lindon Jeremy K Nicholson |
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Institution: | (1) Department of Chemistry, Birkbeck College, University of London, 29, Gordon Square, London WC1H 0PP, UK, GB;(2) Department of Physical Sciences, Wellcome Research Laboratories, Beckenham, Kent BR3 3BS, UK, GB |
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Abstract: | The renal tubular toxicity of various halogenated xenobiotics has been attributed to their enzymatic bioactivation to reactive
intermediates by S-conjugation. A combination of high resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine, renal histopathology and more routinely used clinical chemistry methods has been used to explore
the acute toxic and biochemical effects of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP) up to 48 h following their administration to male
Fischer 344 (F344) rats. In the absence of gross renal pathology, 1H NMR urinalysis revealed increased excretion of the tricarboxylic acid cycle intermediates citrate and succinate following
DCVC administration. In contrast, both DCVHC and TCTFP produced functional defects in the S2 and S3 segments of the proximal tubule that were confirmed histologically. In these cases, 1H NMR urinalysis revealed increased excretion of glucose, L-lactate, acetate and 3-D-hydroxybutyrate (HB) as well as selective amino aciduria (alanine, valine, glutamate and glutamine). The significance of
the proximal nephropathies induced by DCVHC and TCTFP is discussed in relation to biochemical observations on other xenobiotics
that are toxic by similar mechanisms.
Received: 25 April 1994 / Accepted: 13 June 1994 |
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Keywords: | 3-D-hydroxybutyrate Glucose L-lactate 1H NMR urinalysis S-Conjugate-mediated nephrotoxicity S-(1 2-Dichlorovinyl)-L-cysteine S-(1 2-Dichlorovinyl)-L-homocysteine 1 1 2-Trichloro-3 3 3-trifluoro-1-propene |
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