The metabolism and nephrotoxicity of tetrafluoroethylene in the rat.
Exposure of rats to 6000 ppm tetrafluoroethylene for 6 hr produced marked damage to the proximal tubule of the kidney with no effect on the liver. The toxicity was characterized by very high concentrations of urinary glucose and by marked increases in the concentrations of several urinary enzymes. The no observed effect level for a 6-hr exposure was 2000 ppm. Tetrafluoroethylene was metabolized to S-(1,1,2,2-tetrafluoroethyl)glutathione by rat liver fractions in vitro; the reaction was catalyzed by both microsomal and cytosolic glutathione S-transferases. The rate with microsomes was four times that with cytosol fractions. Evidence for this metabolic pathway in vivo has been obtained by the identification of the cysteinylglycine and cysteine conjugates of tetrafluoroethylene in rat bile. Cytochrome P-450 oxidation, a common metabolic route for haloalkenes, does not appear to occur in the metabolism of tetrafluoroethylene. When administered po to rats, the synthetic cysteine conjugate of tetrafluoroethylene causes renal damage identical to that caused by tetrafluoroethylene itself. The conjugate was metabolized by renal slices in vitro giving pyruvate, ammonia, and a reactive species which caused marked inhibition of organic ion transport into slices. Purified renal beta-lyase also cleaved this conjugate giving stoichiometric amounts of pyruvate and ammonia. The nephrotoxicity of tetrafluoroethylene is believed to derive from the hepatic glutathione conjugate of this compound. Following excretion and degradation of this conjugate in bile, the cysteine conjugate is reabsorbed and further metabolized in the kidney by the enzyme beta-lyase to a cytotoxic species.
D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005466:Fluorocarbons / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D005466:Fluorocarbons; D005978:Glutathione; D003545:Cysteine; C015531:tetrafluoroethylene