title: Dose-dependent metabolism of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), an anesthetic degradation product, to mercapturic acids and 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid in rats.
abstract: The volatile anesthetic sevoflurane is degraded in anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), to which humans are exposed. FDVE is metabolized in rats and humans to two alkane and two alkene glutathione S-conjugates that are hydrolyzed to the corresponding cysteine S-conjugates. The latter are N-acetylated to mercapturic acids, or bioactivated by renal cysteine conjugate beta-lyase to metabolites which may react with cellular macromolecules or hydrolyze to 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. FDVE causes nephrotoxicity in rats, which evidence suggests is mediated by renal uptake of FDVE S-conjugates and metabolism by beta-lyase. Although pathways of FDVE metabolism have been described qualitatively, the purpose of this investigation was to quantify FDVE metabolism via mercapturic acid and beta-lyase pathways. Fischer 344 rats underwent 3-h nose-only exposure to FDVE (0 +/- 0, 46 +/- 19, 98 +/- 7, 150 +/- 29, and 220 +/- 40 ppm), and urine was collected for 24 h. Urine concentrations of the mercapturates, N-acetyl-S-(1,1,3,3, 3-pentafluoro-2-fluoromethoxypropyl)-L-cysteine and N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-L- cysteine, the beta-lyase-dependent metabolite 3,3, 3-trifluoro-2-(fluoromethoxy)propanoic acid, and its degradation product trifluorolactic acid, were determined by GC/MS. There was dose-dependent urinary excretion of the alkane mercapturate N-acetyl-S-(1,1,3,3,3-pentafluoro-2-fluoromethoxypropyl)-L- cysteine and 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, while excretion of the alkene mercapturate N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-L- cysteine plateaued at higher FDVE exposures. The alkane:alkene mercapturic acid excretion ratio was between 2:1 and 4:1. Trifluorolactic acid was only rarely observed. Urine excretion of the beta-lyase-dependent metabolite 3,3, 3-trifluoro-2-(fluoromethoxy)propanoic acid was 10-fold greater than that of the combined mercapturates. Results show that FDVE cysteine S-conjugates undergo facile metabolism via renal beta-lyase, particularly in comparison with detoxication by mercapturic acid formation. The quantitative assay developed herein may provide a biomarker for FDVE exposure and relative metabolism via toxification and detoxifying pathways, applicable to animal and human investigations.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: C
authors.initials: C
authors.lastname: Jubert
authors.forename: D K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: G M
authors.initials: GM
authors.lastname: Hoffman
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D008297:Male; D011422:Propionates / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C101817:3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid; D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D011422:Propionates; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D000111:Acetylcysteine