BACKGROUND Cytochrome P450 (P450) is the largest family of enzymatic proteins in the human liver, and its features have been studied in physiology, medicine, biotechnology, and phytoremediation. OBJECTIVE The aim of this study was to assess the catalytic activities of 28 human CYP3A4 alleles by using dronedarone as a probe drug in vitro, including 7 novel alleles recently found in the Han Chinese population. METHODS We expressed 28 CYP3A4 alleles in insect microsomes and incubated them with 1-100 μM of dronedarone at 37 °C for 40 minutes to obtain the metabolites of N-debutyl-dronedarone. RESULTS Compared with the wild type of CYP3A4, the 27 defective alleles can be classified into four categories. Three alleles had no detectable enzyme activity leading to a lack of kinetic parameters of N-debutyl-dronedarone; the other three alleles slightly despaired when it comes to intrinsic clearance values compared with the features of the wild type. Sixteen alleles exhibited 35.91%~79.70% relative values (in comparison to the wild-type) and could be defined as the "moderate decrease group". The rest of the alleles showed a considerable decrease in intrinsic clearance values, ranging from 11.88%~23.34%. Therefore they were classified as a "significantly decreased group". More specifically, 18 CYP3A4 alleles exhibited a substrate inhibition trend toward dronedarone when the concentration rises to 20 μM. CONCLUSION The outcomes of this novel study on the metabolism of dronedarone by CYP3A4 alleles can be used as experimental data support for the individualized use of this modern drug.

中文翻译：

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野生型和 27 种 CYP3A4 变异体对决奈达隆体外代谢的功能分析。

背景技术细胞色素P450（P450）是人类肝脏中最大的酶蛋白家族，其特征已被生理学、医学、生物技术和植物修复研究。目的本研究的目的是评估28个人类CYP3A4等位基因在体外以决奈达隆为探针药物的催化活性，其中包括最近在汉族人群中发现的7个新等位基因。方法 我们在昆虫微粒体中表达 28 个 CYP3A4 等位基因，并将它们与 1-100 μM 决奈达隆在 37 °C 下孵育 40 分钟，以获得 N-二丁基决奈达隆的代谢物。结果与CYP3A4野生型相比，27个缺陷等位基因可分为四类。三个等位基因没有可检测到的酶活性，导致 N-二丁基决奈达隆缺乏动力学参数；与野生型的特征相比，其他三个等位基因的内在清除率值略显绝望。16个等位基因表现出35.91%~79.70%的相对值（与野生型相比），可以定义为“中度下降组”。其余等位基因的内在清除率值显着下降，范围为11.88%~23.34%。因此，他们被归类为“显着减少组”。更具体地说，当浓度升至 20 μM 时，18 个 CYP3A4 等位基因对决奈达隆表现出底物抑制趋势。结论 这项关于 CYP3A4 等位基因对决奈达隆代谢的新研究的结果可以作为这种现代药物个体化使用的实验数据支持。