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

Abstract

The volatile anesthetic sevoflurane is degraded in anesthesia machines to the haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), which can cause renal and hepatic 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 investigation tested the hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluating sulfoxide formation by human and rat liver and kidney microsomes and expressed P450s and flavin 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 human liver 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 only 0 and 30%, respectively. Of the various cytochrome P450s examined, P450s 3A4 and 3A5 had the highest S-oxidase activity toward (Z)-N-Ac-FFVC; P450 3A4 was the predominant enzyme forming 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-FFVC sulfoxidation by human liver microsomes and 15-85% of N-Ac-DFEC sulfoxidation by human liver 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 FDVE S-conjugates undergo P450-catalyzed and nonenzymatic sulfoxidation and that enzymatic sulfoxidation of (Z)-N-Ac-FFVC and N-Ac-DFEC is catalyzed predominantly by P450 3A. The extent of FDVE sulfoxidation in vivo and the toxicologic significance of FDVE sulfoxides remain unknown and merit further investigation.

Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans

“…Cytochrome P450 and flavin-containing monooxygenase (FMO) are two enzymes capable of oxidizing mercapturic acids to their sulfoxides, with CYP3A enzymes being the most active. 41–43 …”

Identification of the Major Urinary Metabolite of the Highly Reactive Cyclopentenone Isoprostane 15-A2t-Isoprostane in Vivo

“…Such sulfoxidation reactions have been shown to be catalyzed by both cytochrome P450s and flavin monooxygenases in rat liver microsomes (24 -26). These reactions have also been shown to occur in human liver microsomes, albeit at a slower rate (27). Reduction of the carbonyl group on the prostane ring most probably occurs after conjugation with GSH.…”

Effect of Surface Conjugation Chemistry on the Sensitivity of Microcantilever Sensors

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