title: Evidence for metabolism of fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product, by cysteine conjugate beta-lyase.
abstract: The volatile anesthetic sevoflurane is degraded to fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), a potent rat nephrotoxin. In rats in vivo, FDVE undergoes glutathione conjugation and metabolism to cysteine conjugates, whose bioactivation by renal cysteine conjugate beta-lyase has been implicated by the protective effects of (aminooxy)acetic acid, an inhibitor of cysteine conjugate beta-lyase. We specifically tested the hypothesis that FDVE is metabolized via the beta-lyase pathway to yield 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. Urine of rats administered FDVE (0.3 mmol/kg) was extracted and derivatized with diazomethane. Headspace GC/MS analysis demonstrated a peak whose retention time and mass spectrum were identical to those of synthetic methyl 3,3,3-trifluoro-2-(fluoromethoxy)-propanoate. Pretreatment of rats with (aminooxy)acetic acid significantly decreased the amount of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid detected in the urine of FDVE-treated animals. The 19F NMR spectrum of urine from rats administered FDVE was consistent with the formation of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, but could not be differentiated from that of FDVE mercapturates, which are also excreted in urine. These results suggest that FDVE undergoes biotransformation via the beta-lyase pathway and beta-lyase-catalyzed metabolism may mediate the nephrotoxicity of this compound.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000378:metabolism; D000818:Animals; D013437:Carbon-Sulfur Lyases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004987:Ethers / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D005461:Fluorine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008190:Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008738:Methyl Ethers; D011422:Propionates / Q000138:chemical synthesis / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D000077149:Sevoflurane
chemical_list: C101817:3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid; D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D011422:Propionates; D000625:Aminooxyacetic Acid; D005461:Fluorine; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase