Iyer R A, Anders M W
Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
Chem Res Toxicol. 1997 Jul;10(7):811-9. doi: 10.1021/tx960196+.
2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (1, Compound A) is a fluoroalkene formed by the base-catalyzed degradation of sevoflurane that is nephrotoxic in rats. Fluoroalkene 1 is a structural analog of other nephrotoxic haloalkenes that undergo glutathione S-conjugate formation and cysteine S-conjugate beta-lyase-dependent bioactivation to reactive intermediates. The present experiments were designed to study the beta-lyase-dependent biotransformation of S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine (4) and S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-L-cysteine (5) by 19F NMR and UV spectroscopy and GC/MS. Incubation of cysteine S-conjugate 4 with rat kidney cytosol or a pyridoxal model system showed the formation of inorganic fluoride, pyruvate, and 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid (9), the expected products of a beta-lyase-catalyzed reaction. The ratio of fluoride to pyruvate ranged from 2.3 to 2.5. The amount of acid 9 formed in the rat kidney cytosol and the pyridoxal model system was, however, less than 5% of the amount of pyruvate formed. Incubation of conjugate 4 with rat kidney cytosol and analysis by 19F NMR spectroscopy showed resonances that were assigned to 3,3,3-trifluorolactic acid (10); the formation of acid 10 was observed in the pyridoxal model only after prolonged incubation (> 18 h). Lactic acid 10 was identified as a degradation product of acid 9. Cysteine S-conjugate 5 was not stable in pH 7.4 buffer and underwent a rapid cyclisation reaction (t1/2 approximately 5 min) to form 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazol e-4 -carboxylic acid (14). These data show that fluoroalkene 1-derived cysteine S-conjugates are substrates for renal beta-lyase and that acid 9 is formed as a terminal product. Acid 9 is, however, unstable and affords lactic acid 10 as a degradation product.
2-(氟甲氧基)-1,1,3,3,3-五氟-1-丙烯（1，化合物A）是一种氟烯烃，由七氟醚在大鼠体内经碱催化降解生成，具有肾毒性。氟烯烃1是其他肾毒性卤代烯烃的结构类似物，这些卤代烯烃会形成谷胱甘肽S-共轭物，并通过半胱氨酸S-共轭物β-裂解酶依赖性生物活化生成反应性中间体。本实验旨在通过19F核磁共振、紫外光谱和气相色谱/质谱研究S-[2-(氟甲氧基)-1,1,3,3,3-五氟丙基]-L-半胱氨酸（4）和S-[2-(氟甲氧基)-1,3,3,3-四氟-1-丙烯基]-L-半胱氨酸（5）的β-裂解酶依赖性生物转化。将半胱氨酸S-共轭物4与大鼠肾胞液或吡哆醛模型系统孵育，结果显示生成了无机氟化物、丙酮酸和2-(氟甲氧基)-3,3,3-三氟丙酸（9），这些都是β-裂解酶催化反应的预期产物。氟化物与丙酮酸的比例在2.3至2.5之间。然而，在大鼠肾胞液和吡哆醛模型系统中生成的酸9的量不到生成的丙酮酸量的5%。将共轭物4与大鼠肾胞液孵育并用19F核磁共振光谱分析，结果显示出归属于3,3,3-三氟乳酸（10）的共振峰；仅在长时间孵育（>18小时）后，才在吡哆醛模型中观察到酸10的生成。乳酸10被鉴定为酸9的降解产物。半胱氨酸S-共轭物5在pH 7.4缓冲液中不稳定，会迅速发生环化反应（半衰期约5分钟），生成2-[1-(氟甲氧基)-2,2,2-三氟乙基]-4,5-二氢-1,3-噻唑-4-羧酸（14）。这些数据表明，氟烯烃1衍生的半胱氨酸S-共轭物是肾β-裂解酶的底物，酸9是最终产物。然而，酸9不稳定，会生成乳酸10作为降解产物。
