In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

Lim, Sharoen Yu Ming; Loo, Jason Siau Ee; Alshagga, Mustafa Ahmed; Alshawsh, Mohammed Abdullah; Ong, Chin Eng; Pan, Yan

doi:10.1016/j.toxrep.2022.03.040

Cited by 11 publications

(12 citation statements)

References 69 publications

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“…Lim et al reported that cathinones, which are similar in structure to amphetamines, inhibit the activity of CYP2D6 and CYP3A4. 9,10 However, the present study showed that the expression of only the CYP2D6 gene was suppressed after MA addition. Additionally, previous studies have reported that MA does not affect CYP3A4 .…”

Section: Discussioncontrasting

confidence: 62%

“…18 The difference between cathinone and MA in terms of the effect on CYP3A4 is unknown, but it may be due to structural differences. 10 The results of the present research lead us to hypothesize that the clock genes inhibit the effect of MA on CYP3A4 expression. In addition, MA may affect not only CYP2D6 and CYP3A4 but also various other CYP isoforms via clock genes.…”

Section: Discussionmentioning

confidence: 66%

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Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression

2022

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This study examined the association between clock gene expression and the effect of methamphetamine (MA) on drug-metabolizing enzymes from the perspective of drug metabolism. The relationship between expression of the clock genes BMAL1 and PER2 and the drug-metabolizing enzymes CYP3A4 and CYP2D6 was investigated using livers from autopsy cases of MA-intoxication deaths. Additionally, the effect of MA exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. Comparisons of the expression of various genes in MA users according to blood MA concentration revealed that CYP3A4 expression was similar to that of PER2, and CYP2D6 expression was similar to that of BMAL1. In cultured cell experiments, BMAL1 and CYP2D6 expression decreased depending on the time elapsed after MA addition, and PER2 and CYP3A4 expression increased slightly in a concentration-dependent manner. These results were consistent with the findings of autopsy examinations. Expression of CYP3A4 and CYP2D6 under BMAL1 and PER2 suppression, but not CYP2D6 under PER2 suppression alone, was upregulated in response to MA. These results suggest that CYPs are regulated via the clock genes BMAL1 and PER2 during MA metabolism.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 66%

Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression

2022

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“…Moreover, fluorescent substrates may interact with CYPs differently than classic drug substrates in the body. 62 Besides that, gastric digestion, absorption of cathine and oral administration first-pass effect also could not be included using the current in vitro screening tool. 62 In addition, the present model system cannot predict enzyme induction, which occurs upon ingestion to some botanicals and their derivatives.…”

Section: Discussionmentioning

confidence: 99%

“…62 Besides that, gastric digestion, absorption of cathine and oral administration first-pass effect also could not be included using the current in vitro screening tool. 62 In addition, the present model system cannot predict enzyme induction, which occurs upon ingestion to some botanicals and their derivatives. The current in vitro method is a simple model, and therefore, further studies should encompass relevant drug substrates with liver microsomes or hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The current in vitro method is a simple model, and therefore, further studies should encompass relevant drug substrates with liver microsomes or hepatocytes. 62 The high flexibility of the CYP active site poses another challenge to our docking analysis to accurately predicting the appropriate substrate binding modes and also the site of metabolism (SOM) of the substrate (e.g. cathine).…”

Section: Discussionmentioning

confidence: 99%

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Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

et al. 2022

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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 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-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.

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Inhibition of Human CYP1A1/A2 by a Hydroalcoholic Extract and Its Neolignan Constituents from Piper rivinoides

Ramos,

de Oliveira Santos,

Marques

et al. 2024

Rev. Bras. Farmacogn.

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In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

Cited by 11 publications

References 69 publications

Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression

Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

Inhibition of Human CYP1A1/A2 by a Hydroalcoholic Extract and Its Neolignan Constituents from Piper rivinoides

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