Staff View: Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s

Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s

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 t...

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Main Authors:	Lim, Sharoen Yu Ming, Loo, Jason Siau Ee, Alshagga, Mustafa, Alshawsh, Mohammed Abdullah, Ong, Chin Eng, Pan, Yan
Format:	Article
Published:	Sage 2022
Subjects:	R Medicine RM Therapeutics. Pharmacology
Online Access:	http://eprints.um.edu.my/41445/
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spelling	my.um.eprints.414452023-09-22T07:53:47Z http://eprints.um.edu.my/41445/ Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s Lim, Sharoen Yu Ming Loo, Jason Siau Ee Alshagga, Mustafa Alshawsh, Mohammed Abdullah Ong, Chin Eng Pan, Yan R Medicine RM Therapeutics. Pharmacology 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. Sage 2022-09 Article PeerReviewed 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 <https://doi.org/10.1177/10915818221103790>. 10.1177/10915818221103790
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	R Medicine RM Therapeutics. Pharmacology
spellingShingle	R Medicine RM Therapeutics. Pharmacology Lim, Sharoen Yu Ming Loo, Jason Siau Ee Alshagga, Mustafa Alshawsh, Mohammed Abdullah Ong, Chin Eng Pan, Yan Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
description	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.
format	Article
author	Lim, Sharoen Yu Ming Loo, Jason Siau Ee Alshagga, Mustafa Alshawsh, Mohammed Abdullah Ong, Chin Eng Pan, Yan
author_facet	Lim, Sharoen Yu Ming Loo, Jason Siau Ee Alshagga, Mustafa Alshawsh, Mohammed Abdullah Ong, Chin Eng Pan, Yan
author_sort	Lim, Sharoen Yu Ming
title	Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
title_short	Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
title_full	Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
title_fullStr	Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
title_full_unstemmed	Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s
title_sort	protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome p450s
publisher	Sage
publishDate	2022
url	http://eprints.um.edu.my/41445/
_version_	1778161673766436864
score	13.211869

Protein-ligand identification and in vitro inhibitory effects of cathine on 11 major human drug metabolizing cytochrome P450s

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