Effect of 95% Ethanol Khat Extract and Cathinone on in vitro Human Recombinant Cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 Activity

Lim, Sharoen Yu Ming; Azidin, Athira Rafhana Binti; Ung, Yee Tze; Alshagga, Mustafa Ahmed; Alshawsh, Mohammed Abdullah; Mohamed, Zahurin; Ong, Chin Eng; Pan, Yan

doi:10.1007/s13318-018-0518-2

Cited by 16 publications

(20 citation statements)

References 38 publications

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“…They result in the feeling of well-being and mental alertness as well as excitement in users, but they have a number of untoward effects as well, which is why their use is banned in many countries. As aforementioned, the previous research shows neither cathine nor cathinone appears to be responsible for the inhibition of cytochrome subenzymes [9,10,12,28]. Therefore, investigating the molecular mechanism of cytochrome subenzymes' inhibition by khat is still very much needed.…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

“…Previously, a number of studies have been carried out to establish the effects of khat on the cytochrome P450 (CYP450) enzyme family [9][10][11]. In one of these studies, the effects of the khat extract on the activity of three in vitro human recombinant cytochrome P450 (CYP)2C9, CYP2D6, and CYP3A4 enzymes were checked and compared with that of cathinone, a constituent of khat [12]. Interestingly, the khat extract was observed to inhibit all three subenzymes with IC 50 of 42, 62, and 18 µg/mL, whereas cathinone showed negligible inhibition of the tested CYPs [12].…”

Section: Introductionmentioning

confidence: 99%

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Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

et al. 2020

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AbstractClopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (P < 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.

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Section: Pharmacokinetic Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

et al. 2020

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“…For most people, chewing khat is a mode of increasing energy and elevating mood (Badedi et al 2020). The psycho-stimulating effect of khat is due to the alkaloid cathinone, which has a similar chemical structure as amphetamine (Lim et al 2019). Although khat is one of Ethiopia's largest crop by area of cultivation and the country's second largest export earner, it is considered an illicit drug crop in an increasing number of countries (Shephard 2012;Cochrane and O'Regan 2016;Carrier and Klantsching 2018).…”

Section: Introductionmentioning

confidence: 99%

Exposure to DDT and HCH congeners and associated potential health risks through khat (Catha edulis) consumption among adults in South Wollo, Ethiopia

Woldetsadik

Simon

Knuth

et al. 2021

Environ Geochem Health

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Khat (Catha edulis) chewing is widespread in the region of East Africa. Even low levels of organochlorine pesticides (OCPs) in khat could induce public health concern. In a market-based study, from five popular khat varieties, a total of 35 composite khat samples were analyzed for dichlorodiphenyltrichloroethane (DDT) and its main transformation products, and four hexachlorocyclohexane (HCH) isomers. Extraction was carried out by quick, easy, cheap, effective, rugged and safe method (QuEChERS). OCP concentrations were determined by head space solid phase microextraction coupled to gas chromatography-mass spectrometry (HS-SPME–GC–MS). Every sample contained β-HCH above the maximum residue limit set by the European Commission. For total DDT, this was the case for 25.7% of the samples. The ratios of (p,p′-DDD + p,p′-DDE) to p,p′-DDT were less than one for 85% of khat samples, demonstrating recent use of DDT in khat farmlands. Conversely, the ratio of β-HCH to total HCH varied from 0.56 to 0.96, implying historical input of technical HCH. Assuming a daily chewable portion of 100 g, dietary intakes of p,p′-DDT, total DDT and total HCH by adults ranged from 3.12 to 57.9, 6.49 to 80.2 and 39.2 to 51.9 ng (kg body weight)−1 day−1, respectively. These levels are below acceptable levels suggested by international organizations. Chewing khat showed lower non-cancer health risk, but showed relatively higher cancer risk in terms of OCPs. Because khat is chewed without being subjected to any treatment, uncertainties associated with estimated intakes and health risks should be low. Therefore, this practice is of great concern.

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“…Time curves were plotted afterwards to define the incubation time for single CYP assays namely 60 minutes for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4 and 120 minutes for CYP3A5, respectively, as determined previously. 25,26 The inhibitory effects of cathine on human CYP enzymes activities were determined using Vivid ® CYP450 Screening Kits 27 The CYP enzyme specific substrates added were as follows: Vivid ® BOMCC (7-benzyloxymethyloxy-3-cyanocoumarin) for CYP2B6, CYP2C9, CYP3A4 and CYP3A5; Vivid ® CC (3-cyanocoumarin) for CYP2A6; Vivid ® DBOMF (dibenzylmethylfluorescein) for CYP2C8; Vivid ® EOMCC (ethoxymethyloxy-3-cyanocoumarin) for CYP1A2, CYP2C19, CYP2D6 and CYP2E1; Vivid ® MOBFC (7-p-methoxybenzyloxy-4-trifluorocoumarin) for CYP2J2; and 0.03 mM NADP + . The mixture was shaken at room temperature, 60 minutes for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4 and 120 minutes for CYP3A5.…”

Section: Determination Of Cyps Activity Using Vivid P450 Assay Kits A...mentioning

confidence: 99%

“…24 Investigations into the inhibitory effects of cathine on CYPs are generally lacking in the literature as most studies about khat-drug interactions have focused on cathinone, which is deemed to be the major active compound in khat. Our earlier study found that khat ethanol extract (KEE) inhibited CYP2C9, CYP2D6 and CYP3A4 significantly, but cathinone showed negligible inhibition on these CYP isoforms in vitro, 25 suggesting that other active constituents in the khat plant such as merucathine, merucathinone, tannins, cathedulins and norephedrine were likely responsible for these inhibitions. Ensuing this study, it was found that KEE also inhibited other major human drug metabolizing CYP isoforms namely CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 except CYP1A2 in vitro.…”

Section: Introductionmentioning

confidence: 99%

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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Effect of 95% Ethanol Khat Extract and Cathinone on in vitro Human Recombinant Cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 Activity

Cited by 16 publications

References 38 publications

Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

Exposure to DDT and HCH congeners and associated potential health risks through khat (Catha edulis) consumption among adults in South Wollo, Ethiopia

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

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