Affordable Access

deepdyve-link
Publisher Website

Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies.

Authors
  • Mendieta-Wejebe, Jessica Elena1
  • Silva-Trujillo, Arianna1
  • Bello, Martiniano2
  • Mendoza-Figueroa, Humberto L2
  • Galindo-Alvarez, Norma Lizeth2
  • Albores, Arnulfo3
  • Tamay-Cach, Feliciano4
  • Rosales-Hernández, Martha Cecilia1
  • Romero-Castro, Aurelio5
  • Correa-Basurto, José2
  • 1 Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.
  • 2 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.
  • 3 Sección de Toxicología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Ciudad de México, México.
  • 4 Laboratorio de Investigación Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.
  • 5 División de Ciencias de la Salud, Universidad de Quintana Roo, Chetumal, México.
Type
Published Article
Journal
The Journal of pharmacy and pharmacology
Publication Date
Apr 19, 2020
Identifiers
DOI: 10.1111/jphp.13270
PMID: 32307724
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 (KM = 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 (Ki = 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. © 2020 Royal Pharmaceutical Society.

Report this publication

Statistics

Seen <100 times