Purpose: To evaluate the inhibition of CYP3A4 activity in human liver microsomes by flavonoids, furanocoumarins and related compounds and investigate possibly more important and potential inhibitors of CYP3A4 in grapefruit juice.
Methods: The effects of various flavonoids and furanocoumarin derivatives on CYP3A4 activity in two human liver microsomal samples was determined using quinine as a substrate. All flavonoids and furanocoumarin derivatives were dissolved in DMSO. In all cases, inhibition activities were compared with activities in control incubations containing 0.2% (v/v) DMSO.
Results: The results showed that the inhibition of quinine 3-hydroxylation (CYP3A4 activity) by bergapten (67%), and quercetin (55%) was greater than naringenin (39%) and naringin (6%), at the same inhibitor concentration of 100 M. The results also demonstrated that the furan ring in the furanocoumarins enhanced the inhibitory effect on CYP3A4 activity. Flavonoids with more phenolic hydroxyl (-OH) groups produced stronger inhibition than those with less hydroxyl groups. Of all the chemicals studied, bergapten (5-methoxypsoralen) with the lowest IC50 value (19-36 microM) was the most potent CYP3A4 inhibitor.
Conclusions: These results suggest that more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4. Bergapten appears to be a potent inhibitor of CYP3A4, and may therefore be primarily responsible for the effect of grapefruit juice on CYP3A4 activity.