Metabolism of hexafluoropropene. Evidence for bioactivation by glutathione conjugate formation in the kidney.

We investigated the metabolism of hexafluoropropene, a nephrotoxic fluoroalkene, in rat liver and kidney subcellular fractions and in rats in vivo. Incubation of hexafluoropropene (1 mM) with microsomes and cytosol in the presence of glutathione (GSH) yielded S-(1,2,3,3,3-pentafluoropropenyl)glutathione (PPFG) and S-(1,1,2,3,3,3-hexafluoropropyl)glutathione (HFPG) as identified by thermospray mass spectrometry and 1H-NMR. In liver microsomes, PFPG formation was predominant (240 nmol/min/mg protein) over HFPG (36 nmol/min/mg), whereas in cytosol, HFPG was the only hexafluoropropene metabolite (136 nmol/min/mg) detectable. In kidney microsomes, GSH-conjugate formation could not be detected; in kidney cytosol, HFPG was exclusively formed (46 nmol/min/mg). Hexafluoropropene inhalation (800 ppm for 1 hr) in rats fitted with a biliary cannula resulted in the biliary elimination of PFPG without detectable formation of HFPG; the exclusively formed urinary metabolite, identified by GC/MS, was N-acetyl-S-(1,1,2,3,3,3-hexafluoropropy)-L-cysteine. The results show that hexafluoropropene is metabolized to two different GSH-conjugates in rat liver and kidney. The data also suggest that hexafluoropropene metabolites formed in the liver and eliminated with bile are not translocated to the kidney and that intrarenal bioactivation by GSH-conjugation may be responsible for hexafluoropropene-induced nephrotoxicity.