Open AccessExploring the biotransformation of N ‐(2‐hydroxyphenyl)‐2‐propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies
Author(s) -
MendietaWejebe Jessica Elena,
SilvaTrujillo Arianna,
Bello Martiniano,
MendozaFigueroa Humberto L.,
GalindoAlvarez Norma Lizeth,
Albores Arnulfo,
TamayCach Feliciano,
RosalesHernández Martha Cecilia,
RomeroCastro Aurelio,
CorreaBasurto José
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13270
Subject(s) - microsome , cytochrome p450 , metabolite , biotransformation , metabolism , in silico , chemistry , pharmacology , biochemistry , valproic acid , in vitro , enzyme , stereochemistry , biology , neuroscience , epilepsy , gene
Objectives 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. Methods 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. Key findings HO‐AAVPA is metabolized by CYP enzymes ( K M = 38.94 µ m ), 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 i = 59.23 µ m ) 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. Conclusion Therefore, rat liver CYP2C11 isoform is able to metabolize HO‐AAVPA.