Metabolic activation of the nephrotoxic haloalkene 1, 1, 2-trichloro-3, 3, 3-trifluoro-1-propene by glutathione conjugation

1, 1, 2-Trichloro-3, 3, 3-trifluoro-1-propene (TCTFP) is structurally closely related to the stable and non-toxic tetrachloroethylene. However, in TCTFP, the trifluoromethyl group enhances chemical reactivity with nucleophiles. This fact suggested that TCTFP may be metabolized intensively by glutathione (GSH) conjugation and therefore, like hexachlorobutadiene, would be expected to be nephrotoxic. We have investigated the nephrotoxicity and metabolism of TCTFP. Administration of 20 and 40 mg/kg to male rats resulted in a large, dose-dependent increase in urinary excretion of γ-glutamyl transpeptidase (GGT) indicative of proximal tubular damage. No increase in plasma transaminase concentrations indicative of liver damage was found. In rats, N- acetyl-S-(1,2- dichloro-3, 3, 3- trifluoro-1- propenyl)- l - cysteine was a major urinary metabolite of TCTFP. TCTFP was transformed by microsomal and cytosolic GSH S-transferases from rat liver to S-(1,2-dichloro-3, 3, 3-trifluoro-1-propenyl)glutathione (DCTFPG) (identified by NMR and mass spectrometry). DCTFPG was toxic to rat renal cortex cells. Inhibition of GGT and cysteine conjugate β-lyase blocked DCTFPG cytotoxicity. These results suggest the following TCTFP bioactivation: conjugation with GSH in the liver, catabolism of the GSH S-conjugate to the cysteine S-conjugate and cleavage of the cysteine S-conjugate by β-lyase with formation of reactive intermediates in the kidney.