人类还原氟烷代谢体外催化细胞色素P450 2 a6和3 a4。

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Spracklin DK, Thummel客,Kharasch ED

人类还原氟烷代谢体外催化细胞色素P450 2 a6和3 a4。

药物金属底座Dispos。1996年9月,24 (9):976 - 83。

PubMed ID

8886607 (在PubMed

]

文摘

麻醉氟烷进行大面积氧化和还原生物转化,导致导致肝毒性的代谢物。氟烷是厌氧减少了细胞色素P450 (P450)挥发性代谢物2-chloro-1, 1-difluoroethene (CDE)和2-chloro-1, 1, 1-trifluoroethane (CTE)。这次调查的目的是确定人类P450同种型(s)负责还原氟烷新陈代谢。从氟烷CDE和CTE形成由人类肝微粒体代谢是由GC / MS分析。氟烷新陈代谢CDE和CTE在还原条件下完全被一氧化碳,这其中牵扯到的专门P450在这个反应。Eadie-Hofstee块CDE和CTE的形成都是非线性,提出多个P450同种型参与。微粒体CDE和CTE形成都抑制40 - 50% P450 2 a6-selective抑制剂(香豆素和8-methoxypsoralen)和55 - 60% P450 3 a4-selective抑制剂(酮康唑和troleandomycin)。P450 1 - 2 b6 - 2 c9/10,和2 d6-selective抑制剂(7 8-benzoflavone furafylline、orphenadrine sulfaphenazole,和奎尼丁)没有显著影响还原氟烷新陈代谢。测量产物的生成催化cDNA-expressed P450亚型的面板显示,最大的CDE形成发生P450 2 a6,其次是P450 3 a4。P450 3 a4 CTE形成最有效的催化剂。 Among a panel of 11 different human livers, there were significant linear correlations between the rate of CDE formation and both 2A6 activity (r = 0.64, p < 0.04) and 3A4 activity (r = 0.64, p < 0.03). Similarly, there were significant linear correlations between CTE formation and both 2A6 activity (r = 0.55, p < 0.08) and 3A4 activity (r = 0.77, p < 0.005). The P450 2E1 inhibitors 4-methylpyrazole and diethyldithiocarbamate inhibited CDE and CTE formation by 20-45% and 40-50%, respectively; however, cDNA-expressed P450 2E1 did not catalyze significant amounts of CDE or CTE production, and microsomal metabolite formation was not correlated with P450 2E1 activity. This investigation demonstrated that human liver microsomal reductive halothane metabolism is catalyzed predominantly by P450 2A6 and 3A4. This isoform selectivity for anaerobic halothane metabolism contrasts with that for oxidative human halothane metabolism, which is catalyzed predominantly by P450 2E1.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
氟烷	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
奎尼丁	细胞色素P450 2 b6	蛋白质	人类	未知的	抑制剂	细节
Sulfaphenazole	细胞色素P450 2 d6	蛋白质	人类	未知的	抑制剂	细节