Stereoselective Metabolism of Omeprazole by Cytochrome P450 2C19 and 3A4: Mechanistic Insights from DFT Study

2018 ◽  
Vol 122 (22) ◽  
pp. 5765-5775 ◽  
Author(s):  
Kalyanashis Jana ◽  
Tusar Bandyopadhyay ◽  
Bishwajit Ganguly
Keyword(s):  
Cytochrome P450 ◽  
Dft Study ◽  
Stereoselective Metabolism ◽  
Cytochrome P450 2C19

Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine, clopidogrel, and prasugrel

Xenobiotica ◽  
2009 ◽  
Vol 00 (00) ◽  
pp. 090901052457079-8
Author(s):  
Y. Nishiya ◽  
K. Hagihara ◽  
A. Kurihara ◽  
N. Okudaira ◽  
N.A. Farid ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Cytochrome ◽  
Cytochrome P450 2C19

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

scholarly journals Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

ACS Omega ◽  
2021 ◽  
Author(s):  
Tunde L. Yusuf ◽  
Segun D. Oladipo ◽  
Sizwe Zamisa ◽  
Hezekiel M. Kumalo ◽  
Isiaka A. Lawal ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Schiff Base ◽  
Crystal Structures ◽  
Dft Study ◽  
Cytochrome P450 3A4

scholarly journals Estimation of polymorphisms in the drug-metabolizing enzyme, cytochrome P450 2C19 gene in six major ethnicities of Pakistan

Bioengineered ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 4442-4451
Author(s):  
Sagheer Ahmed ◽  
Saima Gul ◽  
Muhammad Akhlaq ◽  
Abrar Hussain ◽  
Sidrah Tariq Khan ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolizing Enzyme ◽  
Cytochrome P450 2C19 ◽  
Metabolizing Enzyme

Cytochrome P450 2C19 polymorphism and clopidogrel after MI – Authors' reply

The Lancet ◽  
2009 ◽  
Vol 373 (9670) ◽  
pp. 1172-1173 ◽  
Author(s):  
JP Collet ◽  
JS Hulot ◽  
G Montalescot
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2C19

scholarly journals Identification of Residues 99, 220, and 221 of Human Cytochrome P450 2C19 as Key Determinants of Omeprazole Hydroxylase Activity

1996 ◽  
Vol 271 (21) ◽  
pp. 12496-12501 ◽  
Author(s):  
Gordon C. Ibeanu ◽  
Burhan I. Ghanayem ◽  
Patricia Linko ◽  
Leiping Li ◽  
Lee G. Pedersen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Hydroxylase Activity ◽  
Human Cytochrome ◽  
Cytochrome P450 2C19

In vitro modulatory effects of Andrographis paniculata, Centella asiatica and Orthosiphon stamineus on cytochrome P450 2C19 (CYP2C19)

2011 ◽  
Vol 133 (2) ◽  
pp. 881-887 ◽  
Author(s):  
Yan Pan ◽  
Badrul Amini Abd-Rashid ◽  
Zakiah Ismail ◽  
Rusli Ismail ◽  
Joon Wah Mak ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Centella Asiatica ◽  
Andrographis Paniculata ◽  
Orthosiphon Stamineus ◽  
Cytochrome P450 2C19
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