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
N1 - Publisher Copyright:
© 2020 Royal Pharmaceutical Society
PY - 2020/7/1
Y1 - 2020/7/1
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.
AB - 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.
KW - CYP2C11
KW - HO-AAVPA
KW - rat liver microsomes
KW - valproic acid
UR - http://www.scopus.com/inward/record.url?scp=85083672922&partnerID=8YFLogxK
U2 - 10.1111/jphp.13270
DO - 10.1111/jphp.13270
M3 - Artículo
C2 - 32307724
AN - SCOPUS:85083672922
SN - 0022-3573
VL - 72
SP - 938
EP - 955
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
IS - 7
ER -