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Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies.
J Pharm Pharmacol. 2020 Jul; 72(7):938-955.JP

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.

Authors+Show Affiliations

Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.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.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.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.Sección de Toxicología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Ciudad de México, México.Laboratorio de Investigación Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México.División de Ciencias de la Salud, Universidad de Quintana Roo, Chetumal, 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32307724

Citation

Mendieta-Wejebe, Jessica Elena, et al. "Exploring the Biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an Aryl Valproic Acid Derivative) By CYP2C11, Using in Silico Predictions and in Vitro Studies." The Journal of Pharmacy and Pharmacology, vol. 72, no. 7, 2020, pp. 938-955.
Mendieta-Wejebe JE, Silva-Trujillo A, Bello M, et al. Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies. J Pharm Pharmacol. 2020;72(7):938-955.
Mendieta-Wejebe, J. E., Silva-Trujillo, A., Bello, M., Mendoza-Figueroa, H. L., Galindo-Alvarez, N. L., Albores, A., Tamay-Cach, F., Rosales-Hernández, M. C., Romero-Castro, A., & Correa-Basurto, J. (2020). Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies. The Journal of Pharmacy and Pharmacology, 72(7), 938-955. https://doi.org/10.1111/jphp.13270
Mendieta-Wejebe JE, et al. Exploring the Biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an Aryl Valproic Acid Derivative) By CYP2C11, Using in Silico Predictions and in Vitro Studies. J Pharm Pharmacol. 2020;72(7):938-955. PubMed PMID: 32307724.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies. AU - Mendieta-Wejebe,Jessica Elena, AU - Silva-Trujillo,Arianna, AU - Bello,Martiniano, AU - Mendoza-Figueroa,Humberto L, AU - Galindo-Alvarez,Norma Lizeth, AU - Albores,Arnulfo, AU - Tamay-Cach,Feliciano, AU - Rosales-Hernández,Martha Cecilia, AU - Romero-Castro,Aurelio, AU - Correa-Basurto,José, Y1 - 2020/04/19/ PY - 2020/01/06/received PY - 2020/03/21/accepted PY - 2020/4/21/pubmed PY - 2020/4/21/medline PY - 2020/4/21/entrez KW - CYP2C11 KW - HO-AAVPA KW - rat liver microsomes KW - valproic acid SP - 938 EP - 955 JF - The Journal of pharmacy and pharmacology JO - J. Pharm. Pharmacol. VL - 72 IS - 7 N2 - 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. SN - 2042-7158 UR - https://www.unboundmedicine.com/medline/citation/32307724/Exploring_the_biotransformation_of_N-(2-hydroxyphenyl)-2-propylpentanamide_(an_aryl_valproic_acid_derivative)_by_CYP2C11,_using_in_silico_predictions_and_in_vitro_studies L2 - https://doi.org/10.1111/jphp.13270 DB - PRIME DP - Unbound Medicine ER -