European journal of drug metabolism and pharmacokinetics · 2024
Inhibitory Effect of Two Carbonic Anhydrases Inhibitors on the Activity of Major Cytochrome P450 Enzymes.
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Elbarbry Fawzy A, Ibrahim Tamer M, Abdelrahman Mohamed A, Supuran Claudiu T, Eldehna Wagdy M
Аннотация
BACKGROUND AND OBJECTIVES: Both AW-9A (coumarin derivative) and WES-1 (sulfonamide derivative) were designed and synthesized as potential selective carbonic anhydrase inhibitors and were tested for anticancer activity. This study was undertaken to investigate their potential inhibitory effects on the major human cytochrome P450 (CYP) drug-metabolizing enzymes.
METHODS: Specific CYP probe substrates and validated analytical methods were used to measure the activity of the tested CYP enzymes. Furthermore, in silico simulations were conducted to understand how AW-9A and WES-1 bind to CYP2A6 at a molecular level. Molecular docking experiments were performed using the high-resolution X-ray structure, Protein Data Bank (PDB) ID: 2FDV for CYP2A6.
RESULTS: CYP2E1-catalyzed chlorzoxazone-6'-hydroxylation was strongly inhibited by AW-9A and WES-1 with IC50 values of 0.084 µM and 0.101 µM, respectively. CYP2A6-catalyzed coumarin-7'-hydroxylation was moderately inhibited by AW-9A (IC50 = 4.2 µM). CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were weakly or negligibly inhibited by both agents. Docking studies suggest elevated potential to block the catalytic activity of CYP2A6.
CONCLUSIONS: These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes.
METHODS: Specific CYP probe substrates and validated analytical methods were used to measure the activity of the tested CYP enzymes. Furthermore, in silico simulations were conducted to understand how AW-9A and WES-1 bind to CYP2A6 at a molecular level. Molecular docking experiments were performed using the high-resolution X-ray structure, Protein Data Bank (PDB) ID: 2FDV for CYP2A6.
RESULTS: CYP2E1-catalyzed chlorzoxazone-6'-hydroxylation was strongly inhibited by AW-9A and WES-1 with IC50 values of 0.084 µM and 0.101 µM, respectively. CYP2A6-catalyzed coumarin-7'-hydroxylation was moderately inhibited by AW-9A (IC50 = 4.2 µM). CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were weakly or negligibly inhibited by both agents. Docking studies suggest elevated potential to block the catalytic activity of CYP2A6.
CONCLUSIONS: These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes.