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 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 , S-[2-(fluoromethoxy)-1,3,3, 3-tetrafluoro-1-propenyl]glutathione , S-[2-(fluoromethoxy)-1,1,3,3, 3-pentafluoropropyl]-L-cysteine and S-[2-(fluoromethoxy)-1,3,3, 3-tetrafluoro-1-propenyl]-L-cysteine . Conjugates , and 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 , at a dose of 500 micromol/kg, was hepatotoxic. Cysteine S-conjugate 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 beta-lyase substrate. Also, the alpha-methyl analog of cysteine S-conjugate S-[2-(fluoromethoxy)-1,1,3,3, 3-pentafluoropropyl]-DL-alpha-methylcysteine, which cannot undergo beta-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 beta-lyase-dependent bioactivation.
Iyer
R A
RA
Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA.
Baggs
R B
RB
Anders
M W
MW
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D003545:Cysteine / Q000378:metabolism*; D004987:Ethers / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D005978:Glutathione; D003545:Cysteine