Lim, Sharoen Yu Ming and Loo, Jason Siau Ee and Alshagga, Mustafa and Alshawsh, Mohammed Abdullah and Ong, Chin Eng and Pan, Yan (2022) Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s. International Journal of Toxicology, 41 (5). pp. 355-366. ISSN 1091-5818, DOI https://doi.org/10.1177/10915818221103790.
Full text not available from this repository.Abstract
Cathine is the stable form of cathinone, the major active compound found in khat (Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs' active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 mu M, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in K-i analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with K-i value of 63 and 100 mu M, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and pi-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.
| Item Type: | Article |
|---|---|
| Funders: | University of Nottingham Pump-Priming [54-ER-0-744019] |
| Uncontrolled Keywords: | Cathine; CYP; In vitro; Docking; Herb-drug interaction |
| Subjects: | R Medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 22 Sep 2023 07:53 |
| Last Modified: | 22 Sep 2023 07:53 |
| URI: | http://eprints.um.edu.my/id/eprint/41445 |
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