Vol. 283, Issue 3, 1544-1551, 1997

Nephrotoxicity of the Glutathione and Cysteine S-Conjugates of the Sevoflurane Degradation Product 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) in Male Fischer 344 Rats¹

Ramaswamy A. Iyer, Raymond B. Baggs and M. W. Anders

Departments of Pharmacology and Physiology (R.A.I., M.W.A.) and of Laboratory Animal Medicine (R.B.B.), University of Rochester, Rochester, New York

2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) is a halogenated alkene that is nephrotoxic in rats when administered by inhalation or intraperitoneally. Compound A undergoes glutathione-dependent metabolism: Compound A-derived glutathione S-conjugates and mercapturates are excreted in the bile and urine, respectively, of rats given Compound A. The present experiments were designed to study the nephrotoxicity of the Compound A-derived glutathione and cysteine S-conjugates, S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]glutathione 2, S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]glutathione 3, S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine 4 and S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-L-cysteine 5. Conjugates 2, 3 and 4 given intraperitoneally produced dose-dependent nephrotoxicity that was characterized by diuresis, increased excretion of glucose and protein, elevated blood urea nitrogen concentrations and severe morphological changes in the kidneys, particularly in the proximal tubules. Glutathione S-conjugate 2, at a dose of 500 µmol/kg, was hepatotoxic. Cysteine S-conjugate 5 was not nephrotoxic, apparently because of its facile cyclization to the thiazoline 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazole-4-carboxylic acid, which is not a -lyase substrate. Also, the -methyl analog of cysteine S-conjugate 4 S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-DL--methylcysteine, which cannot undergo -lyase-dependent bioactivation, was not nephrotoxic. These in vivo data show that Compound A-derived S-conjugates are nephrotoxic and that the toxicity is associated with -lyase-dependent bioactivation.