Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations

Worku Bedada,Adrián Llerena,Eleni Aklillu,Fernando De Andrés,Jemal Hussein,Ephrem Engidawork

doi:10.1038/s41598-018-31191-1

Abstract

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.

Highlights

Khat (Catha edulis Forsk) is the most widely used psychoactive herb in the world[1,2]
This study was undertaken to evaluate the effect of Khat use on the metabolic activities of five major drug metabolizing cytochrome P450 (CYP) enzymes in humans (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and the potential influence of pharmacogenetic variations on Khat-CYP enzymes interactions
We investigated the effect of Khat use on the metabolic activities of five major drug metabolizing CYP enzymes and any potential influence of pharmacogenetic variations on the Khat-CYP enzymes interaction

Summary

Introduction

Khat (Catha edulis Forsk) is the most widely used psychoactive herb in the world[1,2]. Before and after first-line phenotype screening studies using cocktail probe substrates approach focusing on five of the major CYP450 enzymes that metabolizes more than 90% of clinically used drugs, namely CYP1A2, 2C9, 2C19, 2D6, and 3A4, predict herb-drug interactions[24,25,26]. In a small sample size preliminary study, we recently reported a significant inhibition of CYP2D6 and a borderline effect on CYP3A4 metabolic activity by Khat use[29]. The effect of Khat use on the other CYP enzymes and the impact of pharmacogenetic variations warrants further investigations. This study was undertaken to evaluate the effect of Khat use on the metabolic activities of five major drug metabolizing CYP enzymes in humans (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and the potential influence of pharmacogenetic variations on Khat-CYP enzymes interactions

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Conclusion