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In Vitro Studies of Intestinal Permeability and Hepatic and Intestinal Metabolism of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops (Humulus lupulus L.)

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Purpose

The absorption potential and metabolism of 8-prenylnaringenin (8-PN) from hops (Humulus lupulus L.) were investigated. 8-PN is a potent estrogen with the potential to be used for the relief of menopausal symptoms in women.

Methods

Monolayers of the human intestinal epithelial cancer cell line Caco-2 and human hepatocytes were incubated with 8-PN to model its intestinal absorption and hepatic metabolism, respectively.

Results

The apparent permeability coefficients for 8-PN in the apical-to-basolateral and basolateral-to-apical directions of a Caco-2 monolayer were 5.2 ± 0.7 × 10−5 and 4.9 ± 0.5 × 10−5 cm/s, respectively, indicating good intestinal absorption via passive diffusion. Both glucuronide and sulfate conjugates of 8-PN were detected in the Caco-2 cell incubations. The 4′-O-glucuronide was the predominant Caco-2 cell metabolite, followed by 7-O-sulfate and 4′-O-sulfate. Both phase I and phase II metabolites of 8-PN were formed by human hepatocytes. The 7-O-glucuronide was the most abundant hepatocyte metabolite, and no sulfate conjugates were detected. Incubations with various cDNA-expressed UDP-glucuronosyltransferases indicated that the isozymes UGT1A1, UGT1A6, UGT1A8, and UGT1A9 were responsible for glucuronidation of 8-PN.

Conclusions

Although orally administered 8-PN should be readily absorbed from the intestine, its bioavailability should be reduced significantly by intestinal and hepatic metabolism.

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Abbreviations

ABCC2 (MRP2):

multidrug-resistance-associated protein-2

AP:

apical

BL:

basolateral

CID:

collision-induced dissociation

CYP:

cytochrome P450

FWHM:

full width at half maximum

HPLC:

high-performance liquid chromatography

LC–MS:

liquid chromatography–mass spectrometry

LC–MS–MS:

liquid chromatography tandem mass spectrometry

TEER:

transepithelial electrical resistance

UGT:

uridine diphosphoglucuronosyltransferase

8-PN:

8-prenylnaringenin

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Acknowledgments

We thank Jim Boyd and Yakima Chief, Inc. (Sunnyside, WA, USA) for providing plant material. This research was supported by grant P50AT00155 provided to the UIC/NIH Center for Botanical Dietary Supplements Research by the Office of Dietary Supplements, the National Institute of General Medical Sciences, the Office for Research on Women's Health, and the National Center for Complementary and Alternative Medicine. The content is the responsibility of the authors and does not necessarily represent the official views of the sponsors.

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Correspondence to Richard B. van Breemen.

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Nikolic, D., Li, Y., Chadwick, L.R. et al. In Vitro Studies of Intestinal Permeability and Hepatic and Intestinal Metabolism of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops (Humulus lupulus L.). Pharm Res 23, 864–872 (2006). https://doi.org/10.1007/s11095-006-9902-8

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