EFFECTS OF FLAVONOIDS ON CYTOCHROME P450-DEPENDENT ACETAMINOPHEN METABOLISM IN RATS AND HUMAN LIVER-MICROSOMES

Flavonoids are widely occurring in our diet. In this study, the effect s of nine flavonoids on acetaminophen (APAP) oxidation and related cyt ochrome P450 (P450) enzyme activities were investigated. With rat live r microsomes, APAP oxidation was stimulated 2- to 4-fold by 50 mu M fl avone or tangeretin and inhibited 65% by myricetin or quercetin. Only a slight inhibition of APAP oxidation was caused by naringenin. All th e effects cited herein were from experiments with 50 mu M flavonoids. With human liver microsomal samples that had high P450 3A4 activity, A PAP oxidation was stimulated 1.6- to 3.0-fold by tangeretin, nobiletin , and flavone, but inhibited 40-60% by myricetin and quercetin. With h uman P450 1A2 expressed in Hep G2 cells, APAP oxidation was inhibited completely by flavone or quercetin. With expressed P450 3A4, this reac tion was stimulated 4-fold by flavone, but inhibited 60% by quercetin. The expressed human P450 2E1-dependent APAP oxidation was only slight ly affected by flavone and quercetin. The mechanisms of the inhibition and stimulation were complex and varied with the different P450 forms and flavonoids used in the system. The O-deethylation of ethoxyresoru fin in rat liver microsomes was effectively inhibited by myricetin (IC 50, 15 mu M) and moderately inhibited by flavone, tangeretin, and quer cetin (IC50, 50-80 mu M); with P450 1A2 in Hep G2 cell microsomes, the activity was markedly inhibited by flavone (IC50 2.5 mu M). The micro somal P450s 2E1 and 3A activities were inhibited by myricetin (IC50 85 -90 mu M), but not effectively inhibited by other flavonoids. This stu dy demonstrates that P450 3A4-dependent oxidation of APAP is inhibited by flavonoids with free hydroxyl groups but enhanced by those without , whereas P450 1A2 dependent reactions are effectively inhibited by al l the flavonoids tested.