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

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 mumol/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 mumol/kg of CTFG or 100 mumol/kg of CTFC produced similar lesions and increases in urine glucose excretion rates and blood urea nitrogen concentrations. Administration of 10 mumol/kg of CTFG produced no discernable effect on the kidneys. CTFG and CTFC did not alter plasma glucose concentrations or plasma glutamate-pyruvate transaminase 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 data presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formation of 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.