Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.
Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.
J Pharm Pharmacol. 2020 Jul;72(7):938-955. doi: 10.1111/jphp.13270. Epub 2020 Apr 19.
N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), has been proposed as a potential anticancer agent due to its improved antiproliferative effects in some cancer cell lines. Although there is evidence that VPA is metabolized by cytochrome P450 2C11 rat isoform, HO-AAVPA CYP-mediated metabolism has not yet been fully explored. Therefore, in this work, the biotransformation of HO-AAVPA by CYP2C11 was investigated.
Kinetic parameters and spectral interaction between HO-AAVPA and CYP were evaluated using rat liver microsomes. The participation of CYP2C11 in metabolism of HO-AAVPA was confirmed by cimetidine (CIM) inhibition assay. Docking and molecular dynamics simulations coupled to MMGBSA methods were used in theoretical study.
HO-AAVPA is metabolized by CYP enzymes (K = 38.94 µm), yielding a hydroxylated metabolite according to its HPLC retention time (5.4 min) and MS analysis (252.2 m/z). In addition, CIM inhibition in rat liver microsomes (K = 59.23 µm) confirmed that CYP2C11 is mainly involved in HO-AAVPA metabolism. Furthermore, HO-AAVPA interacts with CYP2C11 as a type I ligand. HO-AAVPA is stabilized at the CYP2C11 ligand recognition site through a map of interactions similar to other typical CYP2C11 substrates.
Therefore, rat liver CYP2C11 isoform is able to metabolize HO-AAVPA.
N-(2-羟苯基)-2-丙基戊酰胺（HO-AAVPA）是丙戊酸（VPA）的衍生物，由于其在一些癌细胞系中具有改善的增殖抑制作用，因此被提议作为一种潜在的抗癌药物。尽管有证据表明 VPA 是由细胞色素 P450 2C11 大鼠同工酶代谢的，但 HO-AAVPA 的 CYP 介导的代谢尚未得到充分探索。因此，在这项工作中，研究了 CYP2C11 对 HO-AAVPA 的生物转化。
使用大鼠肝微粒体评估 HO-AAVPA 的动力学参数和 CYP 光谱相互作用。通过西咪替丁（CIM）抑制试验确认 CYP2C11 在 HO-AAVPA 代谢中的参与。使用对接和分子动力学模拟结合 MMGBSA 方法进行理论研究。
HO-AAVPA 被 CYP 酶代谢（K = 38.94 µm），根据其 HPLC 保留时间（5.4 min）和 MS 分析（252.2 m/z）生成羟基化代谢物。此外，大鼠肝微粒体中的 CIM 抑制（K = 59.23 µm）证实 CYP2C11 主要参与 HO-AAVPA 的代谢。此外，HO-AAVPA 作为 I 型配体与 CYP2C11 相互作用。HO-AAVPA 通过与其他典型 CYP2C11 底物相似的相互作用图谱稳定在 CYP2C11 配体识别位点。
因此，大鼠肝 CYP2C11 同工酶能够代谢 HO-AAVPA。
