Abstract
The role of breast cancer resistance protein (BCRP/ABCG2) in limiting the brain and testis penetration of xenobiotic compounds in the blood-brain and -testis barriers was investigated using Bcrp–/– mice. Tissue/plasma concentration ratios in the brain (Kp,brain) and testis (Kp,testis) obtained under steady-state conditions were significantly increased in Bcrp–/– mice for PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), N-hydroxyl PhIP, MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), dantrolene, and prazosin. In addition, the Kp,brain of triamterene and the Kp,testis of 4′-hydroxyl PhIP were also significantly increased in Bcrp–/– mice. The effect of functional impairment of Bcrp on the brain uptake of PhIP, dantrolene, and daidzein in Bcrp–/– mice determined using in situ brain perfusion was weaker than that observed on the Kp values. In vitro transcellular transport experiments using cell lines expressing mouse Bcrp or P-glycoprotein (Mdr1a/Abcb1a) showed that, among the tested Bcrp substrates, PhIP, MeIQx, prazosin, and triamterene are common substrates of Bcrp and P-glycoprotein. The Kp values of common substrates exhibited a smaller increase both in the brain and testis of Bcrp–/– mice than expected from the in vitro Bcrp activities. The Bcrp-specific substrates were weak acids, whereas basic or neutral BCRP substrates were also P-glycoprotein substrates. These results suggest that BCRP limits the tissue penetration of xenobiotic compounds in the blood-brain and -testis barriers, but its in vivo importance is also modulated by P-glycoprotein activity.
Footnotes
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This study was supported by Grants-in-Aid for Scientific Research (A) from Japan Society for the Promotion of Science (JSPS) (KAKENHI 17209005 for Y.S.) and for Scientific Research (B) (KAKENHI 18390046 for H.K.) from Japan Society for the Promotion of Science.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019257.
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ABBREVIATIONS: BBB, blood-brain barrier; BTB, blood-testis barrier; ABC, ATP-binding cassette; P-gp, P-glycoprotein; MDR (Mdr in mice), multidrug resistance protein; MRP (Mrp in mice), multidrug resistance-associated protein; BCRP (Bcrp in mice), breast cancer resistance protein; DHEAS, dehydroepiandrosterone sulfate; CFR, corrected flux ratio; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; 4′-OH PhIP, 4′-hydroxyl PhIP; PBS, phosphate-buffered saline; LC/MS, liquid chromatography/mass spectrometry; N-OH PhIP, N-hydroxyl PhIP; Kp,brain, brain/plasma concentration ratio; Kp,testis, testis/plasma concentration ratio; GFP, green fluorescent protein; LC/MS/(MS), liquid chromatography (tandem) mass spectrometry.
- Received October 12, 2007.
- Accepted February 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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