title: Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds.
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 (K(p,brain)) and testis (K(p,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 K(p,brain) of triamterene and the K(p,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 K(p) 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 K(p) 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Enokizono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ose
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D003620:Dantrolene / Q000378:metabolism; D004285:Dogs; D007093:Imidazoles / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011224:Prazosin / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism; D013552:Swine; D013737:Testis / Q000378:metabolism*; D014223:Triamterene / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D007093:Imidazoles; D011810:Quinoxalines; D015262:Xenobiotics; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C095122:multidrug resistance protein 3; D003620:Dantrolene; D014223:Triamterene; D011224:Prazosin