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.