Role of Cytochrome P4503A in Cysteine S-Conjugates Sulfoxidation and the Nephrotoxicity of the Sevoflurane Degradation Product Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in

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• 作者：Pam Sheffels ; Jesara L. Schroeder ; T. Gul Altuntas ; H. Denny Liggitt ; and Evan D. Kharasch
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：September 2004
• 年：2004
• 卷：17
• 期：9
• 页码：1177 - 1189
• 全文大小：947K
• 年卷期：v.17,no.9(September 2004)
• ISSN：1520-5010

文摘

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVEundergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acidconjugates, and cysteine conjugate metabolism by renal ddle">-lyase, which is a bioactivationpathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acidconjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were moretoxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless,the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remainunknown. This investigation determined, in rats in vivo, the existence, role of P4503A, andnephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated withdexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then,nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturatesulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acidsulfoxide metabolites in vivo and their urinary excretion were unambiguously established bymass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivoassessed by renal histology, blood urea nitrogen concentrations, and urine volume and proteinexcretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting ddle">-lyase-dependentFDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. Theseresults demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in ratsin vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugatessulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicificationin rats, in addition to ddle">-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.