For example, the flavonoids, naringenin, quercetin and kaempherol (kaempherol is an antioxidant, a phytoestrogen, and a mutagen) modify the metabolism of estradiol, causing increased bioavailability of both estrone and estradiol. (W. Schubert, et al., “Inhibition of 17-beta-estradiol metabolism by grapefruit juice in ovariectomized women,” Maturitas (Ireland) 30(2-3), 155-163, 1994.) -Ray Peat, PhD
Maturitas. 1994 Dec;20(2-3):155-63.
Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women.
Schubert W, Cullberg G, Edgar B, Hedner T.
In an open, randomized, cross-over study the concentrations of 17 beta-estradiol and estrone in serum were measured over 192 hours in 8 ovariectomized women after a single oral dose intake of 2 mg micronized 17 beta-estradiol. The subjects were studied with and without grapefruit juice intake containing the three natural flavonoids, naringenin, quercetin and kaempherol, which are found as glycosides in citrus fruit. These flavonoids interact with the metabolism of drugs such as 17 beta-estradiol and other steroids that are extensively metabolised through the P-450NF (P-450 IIIA4) enzyme or closely related P-450 systems. After administration of grapefruit juice, peak estrone (between 2-6 hours after tablet intake) concentrations increased significantly. The AUC0-48 and AUC0-192 for estrone but not 17 beta-estradiol, resulting from a single administration of micronized 17 beta-estradiol, were significantly altered. Combined measured estrogens (i.e. 17 beta-estradiol and estrone) also increased significantly. The relationship between the AUCs for 17 beta-estradiol and estrone was not altered by juice intake indicating that a metabolic step after estrone, i.e. further A and/or D ring conversion was inhibited. This study demonstrates that grapefruit juice may alter the metabolic degradation of estrogens, and increase the bioavailable amounts of 17 beta-estradiol and its metabolite estrone, presumably by affecting the oxidative degradation of estrogens. This food interaction may be one factor behind the interindividual variability in 17 beta-estradiol, estrone and estriol serum concentrations after exogenous administration of 17 beta-estradiol to patients.
Eur J Drug Metab Pharmacokinet. 1995 Jul-Sep;20(3):219-24.
Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol.
Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T.
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 preparation from human liver. The flavonoids were added in concentrations of 10, 50, 100, 250 and 500 mumol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibited by all the flavonoids tested. Addition of the flavonoids to the microsome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentrations tested of the respective flavonoid, there was approximately 75-85% inhibition of estriol formation. However, naringenin was a less potent 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 conversion of endogenous as well as exogenous 17 beta-estradiol. This interaction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral administration of 17 beta-estradiol to women.
J Pharmacol Exp Ther. 1992 Jun;261(3):1195-9.
Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice.
Miniscalco A, Lundahl J, Regårdh CG, Edgar B, Eriksson UG.
The effects of naringenin, quercetin and kaempferol, flavonoids found in grapefruit as glycosides, on the metabolism of nifedipine and the enantiomers of felodipine were studied in microsomes from rat and human liver. Flavonoid concentrations of 10, 50 and 100 mumol/l were added to rat liver microsomes. The metabolism of nifedipine, (R)- and (S)-felodipine was inhibited to a similar extent, and the inhibition was dependent on the chemical structure and the concentration of flavonoid. Naringenin had lower inhibitory potency than quercetin and kaempferol. These flavonoids exhibited the same order of inhibitory potency in human liver microsomes. No inhibition of naringenin was found, however, until higher concentrations, 300 and 500 mumol/l, were added. A likely mechanism is inhibition of cytochrome P-450 IIIA4, the isoenzyme that catalyzes the oxidation of the dihydropyridine ring to form the corresponding pharmacologically inactive pyridine metabolite. This is a predominant metabolic step that determines the extent of first-pass extraction of dihydropyridines. Grapefruit juice has been shown recently to increase the p.o. bioavailability of the dihydropyridine calcium antagonists nifedipine and felodipine. The interaction may be explained by an inhibition of the first-pass metabolism by flavonoids in grapefruit juice. Furthermore, the results indicate that the rat may be used for in vivo studies of interactions between flavonoids and dihydropyridines or other drugs that are metabolized by cytochrome P-450 IIIA4.
