Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies
| Autor: | Feliciano Tamay-Cach, Jessica Elena Mendieta-Wejebe, Humberto L. Mendoza-Figueroa, José Correa-Basurto, Martha Cecilia Rosales-Hernández, Aurelio Romero-Castro, Arianna Silva-Trujillo, Norma Lizeth Galindo-Alvarez, Martiniano Bello, Arnulfo Albores |
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| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
Metabolite In silico Pharmaceutical Science Antineoplastic Agents 010402 general chemistry Hydroxylation 01 natural sciences Mixed Function Oxygenases chemistry.chemical_compound Biotransformation Drug Stability Pentanes 0103 physical sciences Animals Cytochrome P450 Family 2 Cell Proliferation Pharmacology 010304 chemical physics biology Chemistry Valproic Acid Cytochrome P450 Metabolism Amides In vitro 0104 chemical sciences Rats Isoenzymes Molecular Docking Simulation Biochemistry Steroid 16-alpha-Hydroxylase Docking (molecular) biology.protein Microsomes Liver Aryl Hydrocarbon Hydroxylases |
| Zdroj: | The Journal of pharmacy and pharmacologyReferences. 72(7) |
| ISSN: | 2042-7158 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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