人类肾脏甲氧氟烷和七氟醚代谢。Intrarenal氟甲氧氟烷的生产作为一个可能的机制肾毒性。

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Kharasch ED,汉,Thummel柯

人类肾脏甲氧氟烷和七氟醚代谢。Intrarenal氟甲氧氟烷的生产作为一个可能的机制肾毒性。

麻醉学。1995年3月,82 (3):689 - 99。doi: 10.1097 / 00000542-199503000-00011。

PubMed ID

7879937 (在PubMed

]

文摘

背景:甲氧氟烷肾毒性是由细胞色素P450-catalyzed代谢有毒代谢物。历史承认的代谢物,氟化物,是肾毒素,甲氧氟烷肾毒性是由等离子体氟浓度超过50 microM。七氟醚也是代谢氟离子,和血浆浓度可能超过50 microM,但七氟醚肾毒性并没有被观察到。甲氧氟烷可能原位肾代谢,而非肝代谢,是一个关键事件导致肾毒性。我们测试是否存在代谢基础这一假设通过检查甲氧氟烷和七氟醚脱氟作用的相对利率由人类肾微粒体。方法:微粒体和细胞溶质从肾脏器官捐赠者的准备。甲氧氟烷和七氟醚代谢测定fluoride-selective电极。人类细胞色素P450亚型导致肾脏新陈代谢麻醉被确定通过使用isoform-selective抑制剂和免疫印迹分析个人肾P450酶类与新陈代谢的P450表示从人类肝互补脱氧核糖核酸库。结果:七氟醚和甲氧氟烷进行脱氟作用由人类肾微粒体。氟化生产依赖于时间,还原型烟酰胺腺嘌呤二核苷酸磷酸,蛋白质浓度和麻醉浓度。 In seven human kidneys studied, enzymatic sevoflurane defluorination was minima, whereas methoxyflurane defluorination rates were substantially greater and exhibited large interindividual variability. Kidney cytosol did not catalyze anesthetic defluorination. Chemical inhibitors of the P450 isoforms 2E1, 2A6, and 3A diminished methoxyflurane and sevoflurane defluorination. Complementary deoxyribonucleic acid-expressed P450s 2E1, 2A6, and 3A4 catalyzed methoxyflurane and sevoflurane metabolism, in diminishing order of activity. These three P450s catalyzed the defluorination of methoxyflurane three to ten times faster than they did that of sevoflurane. Expressed P450 2B6 also catalyzed methoxyflurane defluorination, but 2B6 appeared not to contribute to renal microsomal methoxyflurane defluorination because the P450 2B6-selective inhibitor had no effect. CONCLUSIONS: Human kidney microsomes metabolize methoxyflurane, and to a much lesser extent sevoflurane, to fluoride ion. P450s 2E1 and/or 2A6 and P450 3A are implicated in the defluorination. If intrarenally generated fluoride or other metabolites are nephrotoxic, then renal metabolism may contribute to methoxyflurane nephrotoxicity. The relative paucity of renal sevoflurane defluorination may explain the absence of clinical sevoflurane nephrotoxicity to date, despite plasma fluoride concentrations that may exceed 50 microM.

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药物酶

药物	酶	类	生物	药理作用	行动
甲氧氟烷	细胞色素P450 2 a6	蛋白质	人类	未知的	底物	细节
甲氧氟烷	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
七氟醚	细胞色素P450 2 a6	蛋白质	人类	未知的	底物	细节
七氟醚	细胞色素P450 2 b6	蛋白质	人类	未知的	底物	细节
七氟醚	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节