Uttamsingh V, Iyer R A, Baggs R B, Anders M W
Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
Anesthesiology. 1998 Nov;89(5):1174-83. doi: 10.1097/00000542-199811000-00018.
2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) is formed in the anesthesia circuit by the degradation of sevoflurane. Compound A is nephrotoxic in rats and undergoes metabolism by the mercapturic acid pathway in rats and humans to yield the mercapturates S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L -cysteine (compound 3) and S-[2(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cys teine (compound 5). These experiments were designed to examine the fate and nephrotoxicity of compound A-derived mercapturates in rats.
The deacetylation of compounds 3 and 5 by human and rat kidney cytosol and with purified acylases I and III was measured, and their nephrotoxicity was studied in male Fischer 344 rats. The metabolism of the deuterated analogs of compounds 3 and 5, [acetyl-2H3]S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl ]-N-acetyl-L-cysteine (compound 3-d3) and [acetyl-2H3]S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N -acetyl-L-cysteine (compound 5-d3), respectively, was measured.
Compound 5, but not compound 3, was hydrolyzed by human and rat kidney cytosols and by acylases I and III. 19F nuclear magnetic resonance spectroscopic analysis showed no urinary metabolites of compound 3, but unchanged compound 5 and its metabolites 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazol e-4-carboxylic acid were detected in urine. Compound 5 (250 microM/kg) produced clinical chemical and morphologic evidence of renal injury in two of three animals studied.
Compounds 3 and 5 underwent little metabolism. Compound 5, but not compound 3, was mildly nephrotoxic. These results indicate that compound A-derived mercapturate formation constitutes a detoxication pathway for compound A.
2-（氟甲氧基）-1,1,3,3,3-五氟-1-丙烯（化合物A）由七氟醚在麻醉回路中降解形成。化合物A对大鼠具有肾毒性，在大鼠和人类体内通过硫醚氨酸途径进行代谢，生成硫醚氨酸盐S-[2-（氟甲氧基）-1,1,3,3,3-五氟丙基]-N-乙酰-L-半胱氨酸（化合物3）和S-[2-（氟甲氧基）-1,3,3,3-四氟-1-丙烯基]-N-乙酰-L-半胱氨酸（化合物5）。这些实验旨在研究化合物A衍生的硫醚氨酸盐在大鼠体内的转归和肾毒性。
测定化合物3和5在人和大鼠肾细胞溶质中以及与纯化的酰基转移酶I和III作用下的脱乙酰化反应，并在雄性Fischer 344大鼠中研究它们的肾毒性。分别测定化合物3和5的氘代类似物[乙酰基-2H3]S-[2-（氟甲氧基）-1,1,3,3,3-五氟丙基]-N-乙酰-L-半胱氨酸（化合物3-d3）和[乙酰基-2H3]S-[2-（氟甲氧基）-1,3,3,3-四氟-1-丙烯基]-N-乙酰-L-半胱氨酸（化合物5-d3）的代谢情况。
化合物5可被人和大鼠肾细胞溶质以及酰基转移酶I和III水解，而化合物3则不能。19F核磁共振光谱分析显示，尿液中未检测到化合物3的代谢产物，但检测到未变化的化合物5及其代谢产物2-（氟甲氧基）-3,3,3-三氟丙酸和2-[1-（氟甲氧基）-2,2,2-三氟乙基]-4,5-二氢-1,3-噻唑-4-羧酸。在研究的三只动物中，有两只动物给予化合物5（250μM/kg）后出现了肾损伤的临床化学和形态学证据。
化合物3和5几乎不发生代谢。化合物5具有轻度肾毒性，而化合物3无此毒性。这些结果表明，化合物A衍生的硫醚氨酸盐的形成是化合物A的一种解毒途径。
