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First published on March 5, 2008; DOI: 10.1124/dmd.107.019257

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Received for publication October 15, 2007.
Revised February 27, 2008.
Accepted for publication February 27, 2008.

Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds

Junichi Enokizono 1, Hiroyuki Kusuhara 1, Atsuhi Ose 1, Alfred H. Schinkel 2, Yuichi Sugiyama 1*

1 The University of Tokyo 2 The Netherlands Cancer Institute

* Address correspondence to: E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

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-to-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, N-hydroxyl PhIP, MeIQx, 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, while 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.


Key words: ABC transporters, active transport, blood-brain barrier


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N. Giri, N. Shaik, G. Pan, T. Terasaki, C. Mukai, S. Kitagaki, N. Miyakoshi, and W. F. Elmquist
Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse
Drug Metab. Dispos., August 1, 2008; 36(8): 1476 - 1484.
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