THE NEPHROTOXICITY AND HEPATOTOXICITY OF 1,1,2,2-TETRAFLUOROETHYL-L-CYSTEINE IN THE RAT

Recent studies have shown that tetrafluoroethylene is a renal and hepa tic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and rena l injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with amino oxyacetic acid on the extent of renal injury produced by TFEC. Doses o f greater than or equal to 12.5 mg/kg TFEC produced renal tubular necr osis to the pars recta of the proximal tubules within 24 h in both mal e and female rats. This was associated with an increased kidney to bod y weight ratio and plasma urea at doses of greater than or equal to 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weig ht ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/k g TFEC as judged by plasma urea and histopathology. However, prior tre atment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine con jugate of hexachloro-1,3-butadiene. Thus no major sex difference in ne phrotoxicity in the rat was seen with TFEC, while accumulation of TFEC , or its N-acetyl derived metabolite, into renal proximal tubular cell s via a probenecid sensitive transport system appears to be a key even t in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial for m of this enzyme and thereby prevent the formation of the reactive met abolite. Our acute studies provide no insight concerning the liver car cinogenicity of tetrafluoroethylene.