Flavonoid-drug interactions: effects of anthocyanins and anthocyanidins on CYP2D6

Objective: The cytochrome P450 enzyme CYP2D6 plays an important role in the metabolism of psychoactive drugs. It is estimated that CYP2D6 is involved in the metabolism of about 50% of all psychoactive drugs, including neuroleptic drugs, SSRI, SNRI and tricyclic antidepressants. Since serious side effects were observed when drug intake was combined with consumption of grapefruit juice, there has been substantial interest in the inhibition of cytochrome P450 activity by the constituents of grapefruit juice, e.g. by flavonoids. Methods: Following incubation of membrane preparations containing recombinant human CYP2D6 enzyme with anthocyanins and their aglycons, inhibition of enzyme activity was determined using a chemiluminescent assay. Results and Conclusion: Both anthocyanins and their aglycons, the anthocyanidins, inhibited proteasome activity in a concentration-dependent manner with IC50 values starting at 55,2µmol/L for the anthocyanidin pelargonidin, and exceeding 800µmol/L for the diglycoside anthocyanins pelargonin and cyanin. However, when compared to quinidine, a known inhibitor of CYP2D6, the overall inhibitory activity of all compounds was shown to be 10000-fold weaker. According to earlier data on furanocoumarins from grapefruit extract, critical CYP2D6 inhibition is achieved in the range of 190–900 nM. Future studies are invited to address effects of the above flavonoids on other CYP isoforms for more detailed toxicity profiles.