Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds

PURPOSE. To evaluate the inhibition of CYP3A4 activity in human liver micro somes by flavonoids, furanocoumarins and related compounds and investigate possibly more important and potential inhibitors of CYP3A4 in grapefruit ju ice. METHODS. The effects of various flavonoids and furanocoumarin derivati ves on CYP3A4 activity in two human liver microsomal samples was determined using quinine as a substrate. All flavonoids and furanocoumarin derivative s 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 naringe nin (39%) and naringin (6%), at the same inhibitor concentration of 100 . T he results also demonstrated that the furan ring in the furanocoumarins enh anced the inhibitory effect on CYP3A4 activity. Flavonoids with more phenol ic 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 muM) was the most potent CYP3A4 inhibit or. CONCLUSIONS. These results suggest that more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4. Ber gapten appears to be a potent inhibitor of CYP3A4, and may therefore be pri marily responsible for the effect of grapefruit juice on CYP3A4 activity.