College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
Antimicrob Agents Chemother. 2013 Nov;57(11):5448-56. doi: 10.1128/AAC.00843-13. Epub 2013 Aug 19.
Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.
阿苯达唑和芬苯达唑是广谱驱虫药，广泛代谢形成羟基和亚砜代谢物。虽然 CYP3A 和黄素单加氧酶已被牵连形成亚砜代谢物，但负责形成羟基代谢物的酶尚未确定。在这项研究中，我们使用人肝微粒体和重组细胞色素 P450（P450）来分别表征阿苯达唑和芬苯达唑形成羟基阿苯达唑和羟基芬苯达唑的酶。在 10 种重组 P450 中，CYP2J2 和/或 CYP2C19 是催化阿苯达唑和芬苯达唑羟化的主要酶。阿苯达唑羟化为羟基阿苯达唑主要由 CYP2J2 介导（0.34 μl/min/pmol P450，分别比 CYP2C19 和 CYP2E1 的速率高 3.9 倍和 8.1 倍），而 CYP2C19 和 CYP2J2 有助于芬苯达唑形成羟基芬苯达唑（CYP2C19 和 CYP2J2 的 2.68 和 1.94 μl/min/pmol P450，分别比 CYP2D6 的速率高 11.7 倍和 8.4 倍）。对来自 14 个人肝微粒体样品中羟基阿苯达唑和羟基芬苯达唑形成速率与已知 P450 酶活性之间的相关分析表明，阿苯达唑羟化与 CYP2J2 活性相关，芬苯达唑羟化与 CYP2C19 和 CYP2J2 活性相关。这些发现得到了人肝微粒体中 P450 同工酶选择性抑制研究的支持。总之，我们的数据首次表明阿苯达唑羟化主要由 CYP2J2 催化，而芬苯达唑羟化优先由 CYP2C19 和 CYP2J2 催化。这些数据将有助于理解阿苯达唑和芬苯达唑在体内的药代动力学和药物相互作用。
