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Effects of Khat (Ca...
Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations
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Bedada, W (author)
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de Andres, F (author)
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Engidawork, E (author)
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Hussein, J (author)
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LLerena, A (author)
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- Aklillu, E (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2018-08-24
- 2018
- English.
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 12726-
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https://www.nature.c...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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