Inhibition of Human Cytochrome P450 Enzymes 3A4 and 2D6 by β-Carboline Alkaloids, Harmine Derivatives

beta-Carboline alkaloids are the main chemical constituents of the plant Peganum harmala, while they also could be formed endogenously and found in coffee, alcoholic beverages and tobacco. Considering the fact that the possibility of herb-drug interactions has recently received great attention worldwide, the aim of the current study was to assess the potential for the metabolism-based drug-drug interactions arising from five beta-carboline alkaloids (harmine, harmaline, harmalol, harmol and harmane) from P. harmala in vitro. With microsome incubation assays and UPLC/HPLC methods, the inhibitions on human liver CYP3A4 and CYP2D6 enzymes by those beta-carboline alkaloids were studied kinetically. Harmine, harmol and harmane exhibited noncompetitive inhibition on the activity of CYP3A4 with K(i) values of 16.76, 5.13 and 1.66 mu M, respectively. These beta-carboline alkaloids were also found to be both substrates and inhibitors for CYP2D6. Harmaline, harmine and harmol showed typical competitive inhibition on the activity of CYP2D6 with Ki values of 20.69, 36.48 and 47.11 mu M, respectively. The inhibition of the two major CYP enzymes by those beta-carboline alkaloids suggested that changes in the pharmacokinetics of co-administered drugs were likely to have occurred. Therefore, caution should be exercised for possible drug interactions of medicinal plants containing those beta-carboline alkaloids and CYP substrates. Copyright (C) 2011 John Wiley & Sons, Ltd.