Vol. 30, Issue 2, 148-154, February 2002

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 -Lyase-Catalyzed Metabolism

T. Gul Altuntas and Evan D. Kharasch

Department of Anesthesiology (T.G.A., E.D.K.) and Department of Medicinal Chemistry (E.D.K.), University of Washington, Seattle, Washington

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 -lyase-catalyzed metabolism to reactive intermediates, which may cause nephrotoxicity. Interindividual variability in renal metabolism of FDVE is unknown. Therefore, this investigation quantified -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. -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 -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 (-lyase metabolism and N-deacetylation) and detoxication. This interindividual variability may effect individual susceptibility to the nephrotoxicity of FDVE and other haloalkenes.