参与普罗帕酮n -脱烷基的细胞色素P450酶的鉴定和表征:相互作用电位的分子基础和活性代谢物的可变配置。

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刘国强，郭国强，郭国强，郭国强

参与普罗帕酮n -脱烷基的细胞色素P450酶的鉴定和表征:相互作用电位的分子基础和活性代谢物的可变配置。

中华医学杂志，1993;43(1):120-6。

PubMed ID

8423765 (PubMed视图

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摘要

代谢酶的活性决定了血浆浓度，从而决定了药物的作用。这些酶的鉴定可以预测药物的相互作用潜力和某些途径产生的变异性。抗心律失常的普罗帕酮被广泛生物转化为活性代谢物5-羟基普罗帕酮和n -脱盐基普罗帕酮。而5-羟基化是由CYP2D6催化的，参与n -脱烷基的酶尚未确定。因此，我们通过体外[人肝微粒体，特异性抗体或抑制剂，以及稳定表达的细胞色素P450 (P450)酶]和体内(慢性治疗条件下患者n - desalkylpropaenone的形成)方法表征了参与n - desalkylpropaenone形成的酶。n -脱盐基普罗帕酮的形成可以用Michaelis-Menten动力学来描述。20例人肝脏微粒体片段中n -脱盐基普罗帕酮的最大形成率(Vmax)与CYP1A2 (r = 0.83, p < 0.001)和CYP3A (r = 0.54, p < 0.05)的含量有较强的相关性。体外内在清除率(来自Vmax/Km)表明，在7个人类肝脏中存在广泛的个体间差异(从0.01至0.1 ml/hr/mg蛋白质)。针对CYP3A和CYP1A2的抗体分别抑制了54 +/- 10%和24 +/- 16%的n -脱盐基普罗帕酮的形成。cyp2d6介导的5-羟基普罗帕酮的形成不受这些抗体的影响。 Verapamil (substrate of CYP3A4 and CYP1A2) and midazolam (substrate of CYP3A4) were competitive inhibitors of N-desalkylpropafenone formation (Ki = 70 microM and 25 microM for verapamil and midazolam, respectively). Coding sequences for CYP1A2 and CYP3A4 were inserted in a yeast expression vector and introduced into Saccharomyces cerevisiae strain W(R). Both CYP1A2 and CYP3A4 catalyzed N-dealkylation of propafenone, with specific activities of 0.32 pmol/min/pmol of P450 and 0.16 pmol/min/pmol of P450, respectively. Our data indicate that N-dealkylation of propafenone is mediated via CYP3A4 and CYP1A2. From experiments on the molecular level interactions of propafenone with other drugs that are metabolized by CYP3A4 and CYP1A2 can be predicted. Such interactions have been reported for cyclosporin, rifampicin, warfarin, and theophylline. Moreover, in vitro intrinsic clearances showed a wide interindividual variability. Therefore, variable plasma concentrations of the active metabolite N-desalkylpropafenone are expected in vivo. We tested this hypothesis in 14 patients (dose of 150 mg of propafenone three times per day) during chronic oral therapy and observed steady state plasma concentrations of N-desalkylpropafenone ranging from 4 to 293 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

引用这篇文章的药物银行数据

药物酶

药物	酶	种类	生物	药理作用	行动
奥美拉唑	细胞色素P450 3A4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节
普罗帕酮	细胞色素P450 1A2	蛋白质	人类	未知的	底物 抑制剂	细节
普罗帕酮	细胞色素P450 2D6	蛋白质	人类	未知的	底物 抑制剂	细节