title: Glutathione S-conjugation of the sevoflurane degradation product, fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in human liver, kidney, and blood in vitro.
abstract: Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats and undergoes glutathione-dependent conjugation to form two alkane (G1, G2) and two alkene glutathione S-conjugates (G3, G4), cleavage to cysteine S-conjugates, and beta-lyase-catalyzed metabolism to reactive thionoacyl fluorides, which may react with cellular macromolecules to cause nephrotoxicity. Although similar metabolites have been identified in human urine in vivo, little is known about sites and mechanisms of GSH conjugation in humans. This investigation quantified FDVE-GSH conjugates formed by human hepatic and renal microsomal and cytosolic fractions and blood in vitro. LC-MS/MS analysis identified all four GSH conjugates (G1-G4) formed in all human subcellular fractions. Quantitative analysis indicated that the relative order of formation was G2 > G1 > G4 > G3 with human liver and kidney subfractions. In blood, the order was G1 > G4 > G2 > G3. These results demostrate that FDVE undergoes GSH-dependent conjugation in human liver and kidney microsomes and cytosol as well as blood, which may account for the detection of corresponding mercapturic acids in the urine of patients exposed to FDVE.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Altuntas
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
mesh_terms: D018685:Anesthetics, Inhalation / Q000378:metabolism* / Q000633:toxicity; D002853:Chromatography, Liquid; D003600:Cytosol / Q000378:metabolism; D004987:Ethers / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008738:Methyl Ethers / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D008862:Microsomes, Liver / Q000378:metabolism; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D005978:Glutathione