Sulfoxidation of Cysteine and Mercapturic Acid Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl Ether (Compound A)

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• 作者：T. Gul Altuntas ; Sang B. Park ; and Evan D. Kharasch
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：March 2004
• 年：2004
• 卷：17
• 期：3
• 页码：435 - 445
• 全文大小：164K
• 年卷期：v.17,no.3(March 2004)
• ISSN：1520-5010

文摘

The volatile anesthetic sevoflurane is degraded in anesthesia machines to the haloalkenefluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), which can cause renal andhepatic toxicity in rats. FDVE is metabolized to S-[1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl)ethyl]-L-cysteine (DFEC) and (E) and (Z)-S-[1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl]-L-cysteine [(E,Z)-FFVC], which are N-acetylated to N-Ac-DFEC and (E,Z)-N-Ac-FFVC S-conjugates. Some haloalkene S-conjugates undergo sulfoxidation. This investigationtested the hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluatingsulfoxide formation by human and rat liver and kidney microsomes and expressed P450s andflavin monooxygenases. Rat, and at lower rates human, liver microsomes oxidized (Z)-N-Ac-FFVC and N-Ac-DFEC to the corresponding sulfoxides. Much lower rates of (Z)-N-Ac-FFVC,but not N-Ac-DFEC, sulfoxidation occurred with rat and human kidney microsomes. In humanliver microsomes, the P450 inhibitor 1-aminobenzotriazole completely inhibited S-oxidation,while heating to inactivate FMO decreased (Z)-N-Ac-FFVC and N-Ac-DFEC sulfoxidation only0 and 30%, respectively. Of the various cytochrome P450s examined, P450s 3A4 and 3A5 hadthe highest S-oxidase activity toward (Z)-N-Ac-FFVC; P450 3A4 was the predominant enzymeforming N-Ac-DFEC-SO. The P450 3A inhibitors troleandomycin and ketoconazole inhibited>95% of (Z)-N-Ac-FFVC sulfoxidation by P450 3A4 and 3A5 and 40-100% of (Z)-N-Ac-FFVCsulfoxidation by human liver microsomes and 15-85% of N-Ac-DFEC sulfoxidation by humanliver microsomes. Sulfoxidation of DFEC was also examined in human liver microsomes.Substantial amounts of sulfoxide were observed, even in the absence of NADPH or protein,while enzymatic formation was comparatively minimal. These results show that FDVES-conjugates undergo P450-catalyzed and nonenzymatic sulfoxidation and that enzymaticsulfoxidation of (Z)-N-Ac-FFVC and N-Ac-DFEC is catalyzed predominantly by P450 3A. Theextent of FDVE sulfoxidation in vivo and the toxicologic significance of FDVE sulfoxides remainunknown and merit further investigation.