NEPHROTOXICITY OF S-(2-CHLORO-1,1,2-TRIFLUOROETHYL)GLUTATHIONE AND S-(2-CHLORO-1,1,2-TRIFLUOROETHYL)-L-CYSTEINE, THE GLUTATHIONE AND CYSTEINE CONJUGATES OF CHLOROTRIFLUOROETHENE

  • 1 December 1985
    • journal article
    • research article
    • Vol. 235  (3) , 851-857
Abstract
The glutathione and cysteine conjugates of the nephrotoxin chlorotrifluoroethene, S-(2-chloro-1,1,2-trifluoroethyl)glutathione (CTFG) and S-(2-chloro-1,1,2-trifluoroethyl)cysteine (CTFC), are potent nephrotoxins in male rats. Morphological changes in the kidneys were observed 1.5 hr after giving 100 .mu.mol/kg of CTFG (i.v.) and severe damage to the proximal tubules was evident 24 hr after treatment; this dose of CTFG caused a 100-fold increase in urine glucose excretion, a 10-fold increase in urine protein excretion and a 4-fold increase in blood urea nitrogen concentrations 24 hr after administration. Administration of 50 .mu.mol/kg of CTFG or 100 .mu.mol/kg of CTFC produced similar lesions and increases in urine glucose excretion rates and blood urea nitrogen concentrations. Administration of 10 .mu.mol/kg of CTFG produced no discernible effect on the kidneys. CTFG and CTFC did not alter plasma glucose concentrations or plasma glutamate-pyruvate transamine activities. CTFG and CTFC produced time- and dose-dependent loses of cell viability in isolated rat renal tubular cells. The toxicity of CTFG to isolated renal tubular cells was prevented by the .gamma.-glutamyltransferase inhibitor AT-125, and the toxicity of CTFC and CTFG to isolated cells was prevented by aminooxyacetic acid, an inhibitor of pyridoxal phosphate-dependent enzymes. Moreover, S-(2-chloro-1,1,2-trifluoroethyl)-DL-.alpha.-methylcysteine, which cannot be metabolized by pyridoxal phosphate-dependent enzymes, was not toxic to isolated renal tubular cells. The daa presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formationof a glutathione conjugate, which is metabolized to the ultimate nephrotoxin by the sequential action of renal .gamma.-glutamyltransferase, cysteinylglycine dipeptidase and cysteine conjugate .beta.-lyase.

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