title: P450-dependent and nonenzymatic human liver microsomal defluorination of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product.
abstract: The volatile anesthetic sevoflurane is degraded by strong bases in the carbon dioxide absorbent in clinical anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, also called "Compound A"). FDVE is nephrotoxic in rats, where it is extensively biotransformed. Patients undergoing sevoflurane anesthesia have been exposed to low inhaled concentrations of FDVE. Although sevoflurane renal toxicity under conditions of FDVE formation has not been reported, there is still considerable concern about FDVE metabolism in humans and the potential for FDVE nephrotoxicity. Sevoflurane undergoes P450-catalyzed liver microsomal defluorination. We tested the hypothesis that FDVE also undergoes human liver microsomal defluorination. Defluorination occurred both in the absence and presence of NADPH; rates of total and NADPH-dependent fluoride formation were 1.6 +/- 0.1 and 1 +/- 0.1 nmol.min-1.mg-1 protein (mean +/- SD), respectively, in four human livers. Enzymatic defluorination was linear with respect to time, protein concentration, and was saturable with respect to substrate concentration. NADPH-dependent, but not NADPH-independent, FDVE defluorination was partially inhibited by coumarin, orphenadrine, diethyldithlocarbamate, and 4-methypyrazole. Microsomes containing cDNA-expressed human P4502E1 exhibited substantial catalytic activity toward FDVE defluorination. Microsomal FDVE defluorination was significantly diminished in the presence of the parent anesthetic, sevoflurane, from 1.3 to 0.6 nmol.min-1.mg-1. These results show that FDVE undergoes both P450-catalyzed and nonenzymatic defluorination by human liver microsomes. P4502E1 is implicated in the enzymatic defluorination. Nonenzymatic defluorination may result from FDVE addition to protein thiols. Enzymatic and/or nonenzymatic defluorination may be etiologic factors in FDVE nephrotoxicity in rats. In contrast, P450-dependent FDVE defluorination may be of less clinical consequence in humans, because it is inhibited by the parent anesthetic, sevoflurane.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: D C
authors.initials: DC
authors.lastname: Hankins
mesh_terms: D018685:Anesthetics, Inhalation / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004987:Ethers / Q000378:metabolism*; D005459:Fluorides / Q000032:analysis*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D008738:Methyl Ethers; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; D009249:NADP; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D019392:Cytochrome P-450 CYP2E1; D005459:Fluorides