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

Jessica Elena Mendieta-Wejebe, Arianna Silva-Trujillo, Martiniano Bello, Humberto L. Mendoza-Figueroa, Norma Lizeth Galindo-Alvarez, Arnulfo Albores, Feliciano Tamay-Cach, Martha Cecilia Rosales-Hernández, Aurelio Romero-Castro, José Correa-Basurto

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 (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. Conclusion: Therefore, rat liver CYP2C11 isoform is able to metabolize HO-AAVPA.

    Original languageEnglish
    JournalJournal of Pharmacy and Pharmacology
    DOIs
    StateAccepted/In press - 1 Jan 2020

    Keywords

    • CYP2C11
    • HO-AAVPA
    • rat liver microsomes
    • valproic acid

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