Altuntas T G, Kharasch E D
Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA.
Toxicol Appl Pharmacol. 2001 Dec 1;177(2):85-93. doi: 10.1006/taap.2001.9302.
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats and undergoes glutathione-dependent conjugation to form two alkane (G1, G2) and two alkene glutathione S-conjugates (G3, G4), cleavage to cysteine S-conjugates, and beta-lyase-catalyzed metabolism to reactive thionoacyl fluorides, which may react with cellular macromolecules to cause nephrotoxicity. Although similar metabolites have been identified in human urine in vivo, little is known about sites and mechanisms of GSH conjugation in humans. This investigation quantified FDVE-GSH conjugates formed by human hepatic and renal microsomal and cytosolic fractions and blood in vitro. LC-MS/MS analysis identified all four GSH conjugates (G1-G4) formed in all human subcellular fractions. Quantitative analysis indicated that the relative order of formation was G2 > G1 > G4 > G3 with human liver and kidney subfractions. In blood, the order was G1 > G4 > G2 > G3. These results demostrate that FDVE undergoes GSH-dependent conjugation in human liver and kidney microsomes and cytosol as well as blood, which may account for the detection of corresponding mercapturic acids in the urine of patients exposed to FDVE.
氟甲基 - 2,2 - 二氟 - 1 -（三氟甲基）乙烯基醚（FDVE）是在麻醉机中挥发性麻醉剂七氟醚降解形成的一种氟化烯烃。FDVE对大鼠具有肾毒性，会通过谷胱甘肽依赖性共轭反应形成两种烷烃（G1、G2）和两种烯烃谷胱甘肽S - 共轭物（G3、G4），裂解为半胱氨酸S - 共轭物，并经β - 裂解酶催化代谢为活性硫代酰氟，后者可能与细胞大分子反应导致肾毒性。尽管在人体尿液中已在体内鉴定出类似的代谢产物，但对于人体中谷胱甘肽共轭反应的位点和机制知之甚少。本研究对人肝、肾微粒体和胞质组分以及血液在体外形成的FDVE - 谷胱甘肽共轭物进行了定量分析。液相色谱 - 串联质谱分析鉴定出在所有人亚细胞组分中形成的所有四种谷胱甘肽共轭物（G1 - G4）。定量分析表明，人肝和肾亚组分中形成的相对顺序为G2 > G1 > G4 > G3。在血液中，顺序为G1 > G4 > G2 > G3。这些结果表明，FDVE在人肝和肾微粒体、胞质以及血液中会发生谷胱甘肽依赖性共轭反应，这可能解释了在接触FDVE的患者尿液中检测到相应的硫醚氨酸的原因。
