Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism
Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism
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细胞色素P450 2C9多态性对波生坦代谢的影响
DOI：
10.1124/dmd.114.060244
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发表时间：
2014-11-01
影响因子：
3.9
通讯作者：
Hu, Guoxin
中科院分区：
文献类型：
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作者：
Chen, Mengchun;Zhang, Youting;Hu, Guoxin
细胞色素 P450 (P450) 2C9 是 P450 酶超家族的重要成员，之前报道过 58 个 CYP2C9 等位基因变体。 CYP2C9基因多态性显着影响一些药物的疗效和安全性，可能导致不良反应和治疗失败。本研究的目的是评估 38 个人类 CYP2C9 等位基因（包括在中国汉族人群中发现的 24 个新等位基因 (*36–*60)）对波生坦 (BOS) 的体外催化活性。将表达 38 CYP2C9 等位基因的昆虫微粒体与 10–625 μM 波生坦在 37°C 下孵育 30 分钟，并立即冷却至 -80°C 终止。采用超高效液相色谱-串联质谱系统对 BOS 和 BOS 的主要代谢物羟基波生坦进行了分析。根据与野生型相比的相对清除率值，38个缺陷等位基因可分为三类：与野生型相比，9个等位基因表现出显着增加的内在清除率值（Vmax/Km）（1.5倍~4.9倍相对清除率）；与野生型相比，9 个等位基因表现出显着降低的内在清除率值（0.6-28.9% 相对清除率）。其余 20 个等位基因与野生型相比，酶活性没有显着差异（1 倍）。这些发现表明，在临床使用 BOS 时，应更多关注携带这些罕见 CYP2C9 等位基因的受试者。这是 BOS 代谢所有这些罕见等位基因的首次报告，为 CYP2C9 等位基因的进一步临床研究提供基础数据。
Cytochrome P450 (P450) 2C9 is an important member of the P450 enzyme superfamily, with 58 CYP2C9 allelic variants previously reported. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to assess the catalytic activities of 38 human CYP2C9 alleles, including 24 novel alleles (*36–*60) found in the Han Chinese population, toward bosentan (BOS) in vitro. Insect microsomes expressing the 38 CYP2C9 alleles were incubated with 10–625 μM bosentan for 30 minutes at 37°C and terminated by cooling to −80°C immediately. BOS and hydroxyl bosentan, the major metabolite of BOS, were analyzed by ultra-performance liquid chromatography–tandem mass spectrometry system. Thirty-eight defective alleles can be classified into three categories according to the relative clearance value compared with wild type: nine alleles exhibited significantly increased intrinsic clearance values (Vmax/Km) compared with the wild type (1.5-fold–∼4.9-fold relative clearance); nine alleles exhibited significantly reduced intrinsic clearance values compared with the wild type (0.6–28.9% relative clearance). The remaining 20 alleles exhibited no significant difference (1-fold) in enzyme activity compared with the wild type. These findings suggest that more attention should be directed to subjects carrying these infrequent CYP2C9 alleles when administering BOS in the clinic. This is the first report of all these rare alleles for BOS metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles.