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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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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Title: Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations
Author: Bedada, Worku; Andrés Segura, Fernando de; Engidawork, Ephrem; Hussein, Jemal; Llerena Ruiz, Adrián; Aklillu, Eleni
Abstract: En un estudio cruzado unidireccional, investigamos el efecto del Khat, una planta psicoestimulante natural similar a las anfetaminas, en las actividades catalíticas de cinco importantes enzimas del citocromo P450 (CYP) que metabolizan las drogas. Tras una semana de abstinencia de Khat, se fenotipó a 63 varones voluntarios etíopes utilizando drogas de sonda de cóctel (cafeína, losartán, dextrometorfano, omeprazol). El fenotipado se repitió después de una semana de uso diario de 400 g de hojas frescas de Khat. Se hizo el genotipado para CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5. Se cuantificaron las concentraciones de catinona y fenilpropanolamina urinarias, y de drogas de sonda de plasma y metabolitos mediante LC-MS/MS. Se evaluó el efecto del Khat en las actividades enzimáticas comparando las proporciones metabólicas (MR) de cafeína/paraxantina (CYP1A2), losartán/ácido carboxílico losartán (CYP2C9), omeprazol/5-hidroxiomeprazol (CYP2C19), dextrometorfano/dextrorfano (CYP2D6) y dextrometorfano/3-metoximorfano (CYP3A4) antes y después del uso del Khat. La prueba del par de Wilcoxon indicó un aumento significativo en la mediana de la RM de CYP2D6 (41%, p < 0,0001), y un aumento marginal en la RM de CYP3A4 y CYP2C19 por el Khat. La medida repetida ANOVA indicó el impacto del genotipo CYP1A2 y CYP2C19 en las interacciones de las enzimas Khat-CYP. La mediana de la RM aumentó un 35% en CYP1A2*1/*1 (p = 0,07) y un 40% en los portadores de alelos CYP2C19 defectuosos (p = 0,03). Las proporciones logarítmicas de catinona/fenilpropanolamina en la orina se correlacionaron significativamente con el genotipo CYP2D6 (p = 0,004) y la RM de CYP2D6 (p = 0,025). El khat inhibe significativamente el CYP2D6, inhibe marginalmente el CYP3A4 y, dependiendo del genotipo, inhibe las actividades enzimáticas del CYP2C19 y el CYP1A2.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.
URI: http://hdl.handle.net/10662/10624
Date: 2018


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