FLAVONOIDS IN GRAPEFRUIT JUICE INHIBIT THE IN-VITRO HEPATIC-METABOLISM OF 17-BETA-ESTRADIOL

Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome prepa ration from human liver. The flavonoids were added in concentrations o f 10, 50, 100, 250 and 500 mu mol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibite d by all the flavonoids tested. Addition of the flavonoids to the micr osome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentra tions tested of the respective flavonoid, there was approximately 75-8 5% inhibition of estriol formation. However, naringenin was a less pot ent inhibitor of 17 beta-estradiol metabolism as compared to quercetin and kaempferol. The most likely mechanism of action of the flavonoids on 17 beta-estradiol metabolism is inhibition of the cytochrome P-450 IIIA4 enzyme, which catalyzes the reversible hydroxylation of 17 beta -estradiol into estrone and further into estriol. These hydroxylation processes represent the predominant steps of the hepatic metabolic con version of endogenous as well as exogenous 17 beta-estradiol. This int eraction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral adm inistration of 17 beta-estradiol to women.