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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.
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Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.

机译：五个不同的人类细胞色素在体外介导阿米替林N-去甲基化：CYP 2C19和3A4的优势。

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摘要

The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N-demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.
机译：结合酶动力学和化学抑制研究，已经鉴定了介导阿米替林N-去甲基化的人细胞色素P450（CYP）。来自微粒体的微粒体将表达人类CYP 1A2、2C9、2C19、2D6和3A4的cDNA转染了阿米替林N-去甲基化为去甲替林。 CYP 2E1没有显示可检测的活性。 CYP 2C19和CYP 2D6表现出高亲和力，而CYP 3A4表现出低亲和力。 CYP 2C9和1A2表现出中等亲和力。根据这些动力学参数和人类肝脏中不同CYP的估计相对丰度，CYP 2C19被确定为低阿米替林（治疗相关）浓度下的主要阿米替林N-去甲基酶，而CYP 3A4在更高阿米替林浓度下可能更重要。用酮康唑和奥美拉唑进行的化学抑制研究表明，CYP 3A4是100μmol/ L阿米替林的主要阿米替林N-脱甲基酶，而CYP 2C19在5μmol/ L的底物浓度下同样重要。 CYP 1A2抑制剂α-萘黄酮和CYP 2C9抑制剂磺胺苯并唑在两种底物浓度下对阿米替林N-去甲基化的抑制作用要小得多。奎尼丁没有产生可检测的抑制作用。人肝微粒体阿米替林N-去甲基化的动力学与两种酶模型一致，高亲和力组分表现出Michaelis Menten动力学，低亲和力组分表现出Hill酶动力学。与其他两个具有相对正常2C19活性的样品相比，在两个具有较低CYP 2C19活性水平的肝样品中，阿米替林N-去甲基化动力学没有明显差异。这可能反映出较高的底物浓度值在体外动力学参数估计中的重要性。

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