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

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.