Abstract
The effect of breast cancer resistance protein (Bcrp/Abcg2) on the disposition of the phytoestrogens daidzein, genistein, and coumestrol was investigated using Bcrp-/- mice. Expression of the genes for either mouse Bcrp or human BCRP in MDCK II cells induced apically directed transport of the three phytoestrogens, whereas their transcellular transport was identical in mock and LLC-PK1 cells expressing mouse Mdr1a. After oral administration, the plasma levels of daidzein and genistein were increased in Bcrp-/- mice, but only a minimal change was observed for coumestrol. At steady state, tissue-to-plasma concentration ratios of the three phytoestrogens in the brain and testis of wild-type mice were very small and similar to those of [14C]inulin, whereas those were significantly increased in the brain and testis of Bcrp-/- mice. The largest increases were observed with genistein (9.2- and 5.8-fold in the brain and testis, respectively). The distributions of genistein in the epididymis and fetus, but not the ovary, were also increased in Bcrp-/- mice. The Bcrp protein was localized in the luminal membrane of the endothelial cells in the testis and the body of the epididymis and in both the luminal and abluminal side of ducts in the head of the epididymis. These results suggest that Bcrp limits the oral availability and distribution into the brain and testis, epididymis, and fetus of phytoestrogens.
Footnotes
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This work was supported by a Health and Labour Sciences Research Grant from Ministry of Health, Labour and Welfare for the Research on Advanced Medical Technology (to Y.S.), and by a grant-in-aid for scientific research (B) from Japan Society for the Promotion of Science (KAKENHI 18390046 to H.K.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.034751.
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ABBREVIATIONS: Bcrp, breast cancer resistance protein; mBcrp, mouse breast cancer resistance protein, hBCRP; human breast cancer resistance protein; GFP, green fluorescent protein; L-Mdr1a, LLC-PK1 cells expressing mouse Mdr1a; AUC, area under the curve; Kp, tissue-to-plasma concentration ratio; PCR, polymerase chain reaction; BSA, bovine serum albumin; PBS, phosphate-buffered saline; LC, liquid chromatography.
- Received February 4, 2007.
- Accepted July 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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