Evidence for metabolism of fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product, by cysteine conjugate beta-lyase.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Spracklin, DK; Kharasch, ED

Published Date

  • June 1996

Published In

Volume / Issue

  • 9 / 4

Start / End Page

  • 696 - 702

PubMed ID

  • 8831812

Pubmed Central ID

  • 8831812

Electronic International Standard Serial Number (EISSN)

  • 1520-5010

International Standard Serial Number (ISSN)

  • 0893-228X

Digital Object Identifier (DOI)

  • 10.1021/tx9502103

Language

  • eng