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

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 Sconjugates, 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 Ndeacetylation) and detoxication. This interindividual variability may effect individual susceptibility to the nephrotoxicity of FDVE and