Köster U, Mayer D, Deger H M, DeKant W
Department of Toxicology, University of Würzburg, Germany.
Drug Metab Dispos. 1996 Aug;24(8):906-10.
The biotransformation of the aerosol propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) was investigated in rats in vivo and in rat and human liver microsomes. In the urine of rats exposed to 5000 ppm HFA-227 for 6 hr, very small amounts of hexafluoroacetone trihydrate were identified as an HFA-227 metabolite by 19F-NMR. Fluoride concentrations in the urine samples (0-48 hr after the end of the exposure) from exposed animals were not significantly different from those found in samples from nonexposed rats. In rat and human liver microsomes, fluoride and hexafluoroacetone trihydrate formation from HFA-227 was detected in very low levels only in liver microsomes from pyridine-treated rats and in two of eight human liver microsome samples, which exhibited the highest cytochrome P4502E1 activities. Because some aldehydes may covalently bind to proteins and the formation of fluorinated protein adducts has been implicated in immune-mediated hepatitis induced by halothane, the binding of hexafluoroacetone trihydrate to proteins was also investigated. Hexafluoroacetone trihydrate also gave only a very small resonance in fluorine NMR experiments when binding to human serum albumin was studied in comparison with the acylating agent S-ethyltrifluoroacetate. Moreover, no fluorine-containing products were formed by the reaction of hexafluoroacetone trihydrate with N alpha-acetyl-L-lysine, and hexafluoroacetone trihydrate was not metabolized to fluorine-containing metabolites or inorganic fluoride in rats. Comparative studies in human liver microsomes demonstrated that a halothane metabolite may covalently bind to proteins; in contrast, metabolism and covalent binding of HFA-227 could not be demonstrated. In summary, these data indicate that HFA-227 is biotransformed at very low rates to hexafluoroacetone trihydrate but irreversible binding of hexafluoroacetone trihydrate cannot be demonstrated, even with the application of very sensitive methods, and is considered unlikely, based on the combination of the results obtained.
在大鼠体内以及大鼠和人肝脏微粒体中研究了气溶胶推进剂1,1,1,2,3,3,3 - 七氟丙烷（HFA - 227）的生物转化。在暴露于5000 ppm HFA - 227 6小时的大鼠尿液中，通过19F - NMR鉴定出极少量的六氟丙酮三水合物作为HFA - 227的代谢产物。暴露动物尿液样本（暴露结束后0 - 48小时）中的氟化物浓度与未暴露大鼠样本中的氟化物浓度无显著差异。在大鼠和人肝脏微粒体中，仅在经吡啶处理的大鼠的肝脏微粒体以及八个人肝脏微粒体样本中的两个样本中检测到极少量由HFA - 227形成的氟化物和六氟丙酮三水合物，这两个样本表现出最高的细胞色素P4502E1活性。由于一些醛可能与蛋白质共价结合，并且氟代蛋白质加合物的形成与氟烷诱导的免疫介导性肝炎有关，因此还研究了六氟丙酮三水合物与蛋白质的结合。与酰化剂S - 乙基三氟乙酸酯相比，在研究六氟丙酮三水合物与人血清白蛋白结合时，其在氟核磁共振实验中也仅产生非常小的共振信号。此外，六氟丙酮三水合物与Nα - 乙酰 - L - 赖氨酸反应未形成含氟产物，并且在大鼠中六氟丙酮三水合物未代谢为含氟代谢产物或无机氟化物。在人肝脏微粒体中的比较研究表明，氟烷代谢产物可能与蛋白质共价结合；相比之下，未证明HFA - 227的代谢和共价结合。总之，这些数据表明HFA - 227以非常低的速率生物转化为六氟丙酮三水合物，但即使应用非常灵敏的方法也未证明六氟丙酮三水合物的不可逆结合，基于所获得的结果综合考虑，认为这种情况不太可能发生。
