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 RATS

2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) is a ha logenated alkene that is nephrotoxic in rats when administered by inha lation or intraperitoneally. Compound A undergoes glutathione-dependen t metabolism: Compound A-derived glutathione S-conjugates and mercaptu rates are excreted in the bile and urine, respectively, of rats given Compound A. The present experiments were designed to study the nephrot oxicity of the Compound A-derived glutathione and cysteine S-conjugate s, romethoxy)-1,1,3,3,3-pentafluoropropyl]glutathione 2, ethoxy)-1,3,3 ,3-tetrafluoro-1-propenyl]glutathione 3, romethoxy)-1,1,3,3,3-pentaflu oropropyl]-L-cysteine 4 and ethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-L- cysteine 5. Conjugates 2, 3 and 4 given intraperitoneally produced dos e-dependent nephrotoxicity that was characterized by diuresis, increas ed excretion of glucose and protein, elevated blood urea nitrogen conc entrations and severe morphological changes in the kidneys, particular ly in the proximal tubules. Glutathione S-conjugate 2, at a dose of 50 0 mu mol/kg, was hepatotoxic. Cysteine S-conjugate 5 was not nephrotox ic, apparently because of its facile cyclization to the thiazoline flu oroethyl]-4,5-dihydro-1,3-thiazole-4-carboxylic acid, which is not a b eta-lyase substrate. Also, the alpha-methyl analog of cysteine S-conju gate 4 ,3,3,3-pentafluoropropyl]-DL-alpha-methylcysteine, which cannot undergo beta-lyase-dependent bioactivation, was not nephrotoxic. Thes e in vivo data show that Compound A-derived S-conjugates are nephrotox ic and that the toxicity is associated with beta-lyase-dependent bioac tivation.