Biotransformation of L-cysteine S-conjugates and N-acetyl-L-cysteine S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in human kidney in vitro: interindividual variability in N-acetylation, N-deacetylation, and beta-lyase-catalyzed metabolism.
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE; 1) is a fluoroalkene formed by the base-catalyzed degradation of the anesthetic sevoflurane. FDVE is nephrotoxic in rats. In both rats and humans, FDVE undergoes glutathione-dependent conjugation, cleavage to cysteine S-conjugates, and renal beta-lyase-catalyzed metabolism to reactive intermediates, which may cause nephrotoxicity. Interindividual variability in renal metabolism of FDVE is unknown. Therefore, this investigation quantified beta-lyase-catalyzed bioactivation and N-acetyltransferase-catalyzed inactivation of FDVE cysteine S-conjugates and reactivation of mercapturates by N-deacetylase in cytosol and microsomes from 20 human kidneys. In cytosol, N-acetylation ranged from 0.008 to 0.045 (0.024 +/- 0.01) nmol of mercapturate/mg/min and 0.001 to 0.07 (0.024 +/- 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteine S-conjugates, respectively. Similar results for microsomal N-acetylation were obtained; N-acetylation ranged from 0.005 to 0.055 (0.025 +/- 0.02) nmol of mercapturate/mg/min and 0.001 to 0.06 (0.030 +/- 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteine S-conjugates, respectively. Beta-lyase-catalyzed metabolism to pyruvate varied from 0.004 to 0.14 (0.051 +/- 0.04) nmol/mg/min and from 0.10 to 0.40 (0.26 +/- 0.08) nmol/mg/min for alkane and alkene cysteine-S-conjugates, respectively. N-deacetylation of mercapturates ranged from 0.8 to 2.5 (1.25 +/- 0.57) nmol of cysteine S-conjugate formed/mg/min and 0.05 to 0.37 (0.17 +/- 0.10) nmol of cysteine S-conjugate formed/mg/min for alkane and alkene FDVE mercapturates. Cytosolic cysteine S-conjugates metabolism by renal beta-lyase predominated over N-acetylation (ratio of activities was 0.2-6 and 3-146 for the alkane and alkene cysteine S-conjugates). N-deacetylation predominated over N-acetylation (ratio of activities was 20-205 and 2-54 for alkane and alkene S-conjugates). There was considerable (up to 50-fold) interindividual variability in rates of FDVE toxication (beta-lyase metabolism and N-deacetylation) and detoxication. This interindividual variability may effect individual susceptibility to the nephrotoxicity of FDVE and other haloalkenes.
Gul Altuntas
T
T
Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA.
Kharasch
Evan D
ED
D000107:Acetylation; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D018685:Anesthetics, Inhalation / Q000378:metabolism; D001711:Biotransformation; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004987:Ethers / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology*; D008190:Lyases / Q000378:metabolism; D008738:Methyl Ethers / Q000378:metabolism*; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D004987:Ethers; D016166:Free Radical Scavengers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; D003545:Cysteine; D000111:Acetylcysteine