细胞色素P450 2 e1是人类的主要催化剂氧化氟烷代谢体外。

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Spracklin DK,汉,费舍尔JM, Thummel KE, Kharasch ED

细胞色素P450 2 e1是人类的主要催化剂氧化氟烷代谢体外。

J Exp其他杂志》1997年4月,281(1):400 - 11所示。

PubMed ID

9103523 (在PubMed

]

文摘

挥发性麻醉剂氟烷经历大量的生物转化生成调节肝毒性的代谢物。耗氧,氟烷进行细胞色素P450-catalyzed氧化三氟乙酸(组织)、溴化和被动中间乙醯化肝蛋白质。这些蛋白质neo-antigens刺激免疫反应介导严重肝坏死(“氟烷肝炎”)。这次调查发现人类P450同种型(s),催化氧化氟烷新陈代谢。氟烷氧化由人类肝脏微粒体是由组织评估和溴化的形成。Eadie-Hofstee块组织和溴化的形成都是非线性的,表明多个p450的参与。微粒体组织和溴化形成抑制45 - 66%,21至26%,分别由P450 2 a6抑制剂8-methoxypsoralen和香豆素,90%到84的P450 2 e1抑制剂4-methylpyrazole和二乙基二硫代氨基甲酸55%,抑制剂的P450 2 a6和2 e1。的选择性抑制剂p450 1 a、2 b6, 2 c9/10 2 d6和3 a4并不影响氟烷氧化。在饱和浓度氟烷(2.4卷%)只有cDNA-expressed P450 2 a6和2 b6催化溴化重要的组织和形成,以及P450 2 e1催化相对最小的氧化。相反,在subsaturating氟烷浓度(0.30卷%),代谢由P450 2 e1超过P450 2 a6。 Among a panel of human liver microsomes, there were significant linear correlations between halothane oxidation and P450 2A6 activity and protein content at saturating halothane concentrations (2.4 vol%), and a significant correlation between metabolite formation and P450 2E1 activity (but not P450 2A6 activity) at subsaturating concentrations (0.12 vol%). These experiments suggested P450 2A6 and 2E1 as the predominant catalysts at saturating and subsaturating halothane concentrations, respectively. Further kinetic analysis using cDNA-expressed P450 and liver microsomes clearly demonstrated that P450 2E1 is the high affinity/low capacity isoform (Km = 0.030-0.053 vol%) and P450 2A6 is the low affinity/high capacity isoform (Km = 0.77-1.2 vol%). Evidence was also obtained for substrate inhibition of P450 2E1. The in vitro clearance estimates (Vmax/Km) for microsomal P450 2E1 (4.3-5.7 ml/min/g) were substantially greater than those for microsomal P450 2A6 (0.12-0.21). These clearances, as well as rates of apparent halothane oxidation predicted from kinetic parameters in conjunction with plasma halothane concentrations measured during clinical anesthesia in humans, demonstrated that both P450 2E1 and P450 2A6 participate in human halothane metabolism, and that P450 2E1 is the predominant catalytic isoform.

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药物酶

药物	酶	类	生物	药理作用	行动
氟烷	细胞色素P450 2 e1	蛋白质	人类	未知的	底物	细节