Evidence for Metabolism of Fluoromethyl 2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A), a Sevoflurane Degradation Product, by Cysteine Conjugate β-Lyase

Abstract

The volatile anesthetic sevoflurane is degraded to fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), a potent rat nephrotoxin. In rats in vivo, FDVE undergoes glutathione conjugation and metabolism to cysteine conjugates, whose bioactivation by renal cysteine conjugate beta-lyase has been implicated by the protective effects of (aminooxy)acetic acid, an inhibitor of cysteine conjugate beta-lyase. We specifically tested the hypothesis that FDVE is metabolized via the beta-lyase pathway to yield 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. Urine of rats administered FDVE (0.3 mmol/kg) was extracted and derivatized with diazomethane. Headspace GC/MS analysis demonstrated a peak whose retention time and mass spectrum were identical to those of synthetic methyl 3,3,3-trifluoro-2-(fluoromethoxy)-propanoate. Pretreatment of rats with (aminooxy)acetic acid significantly decreased the amount of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid detected in the urine of FDVE-treated animals. The 19F NMR spectrum of urine from rats administered FDVE was consistent with the formation of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, but could not be differentiated from that of FDVE mercapturates, which are also excreted in urine. These results suggest that FDVE undergoes biotransformation via the beta-lyase pathway and beta-lyase-catalyzed metabolism may mediate the nephrotoxicity of this compound.

Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylation,N-Deacetylation, and β-Lyase-Catalyzed Metabolism

“…It has been shown that FDVE undergoes GSH-and ␤-lyase-dependent biotransformation in rats in vitro and in vivo (Jin et al, 1995(Jin et al, , 1996Anders, 1996, 1997;Spracklin and Kharasch, 1996; and in humans in vitro and in vivo Uttamsingh et al, 1998;. The cysteine S-conjugates were biotransformed to pyruvate, a known product of the ␤-lyase-catalyzed ␤-elimination reaction of cysteine S-conjugates Anders, 1996, 1997).…”

“…1, 8) Anders, 1996, 1997;Spracklin and Kharasch, 1996;Iyer et al, 1998;. The latter has been identified in rat urine by 19 F NMR and GC/MS (Spracklin and Kharasch, 1996;. Cysteine S-conjugates are metabolized by human kidney cytosol and mitochondria in vitro (Iyer and Anders, 1996).…”

“…1, 3), which undergo cleavage to the corresponding cysteine S-conjugates (Fig. 1, 4 and 5) (Jin et al, 1995(Jin et al, , 1996Spracklin and Kharasch, 1996). In rats, N-acetylation forms the mercapturates, two alkane S- [2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-Lcysteine diastereomes (Fig.…”

“…1, 6) and (E)-and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cysteine ( Fig. 1, 7), which are excreted in urine, as identified by ion-spray LC-tandem mass spectrometry, 19 F NMR, and selected-ion mode GC/MS (Jin et al, 1995;Spracklin and Kharasch, 1996;Iyer et al, 1998). The cysteine S-conjugates are also metabolized by rat renal ␤-lyase in vitro and in vivo to reactive intermediates, which may bind to cellular macromolecules or undergo hydrolysis to 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid ( Fig.…”

“…The cysteine S-conjugates are also metabolized by rat renal ␤-lyase in vitro and in vivo to reactive intermediates, which may bind to cellular macromolecules or undergo hydrolysis to 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid ( Fig. 1, 8) Anders, 1996, 1997;Spracklin and Kharasch, 1996;Iyer et al, 1998;. The latter has been identified in rat urine by 19 F NMR and GC/MS (Spracklin and Kharasch, 1996;.…”