TY - JOUR T1 - Breast Cancer Resistance Protein Exports Sulfated Estrogens but Not Free Estrogens JF - Molecular Pharmacology JO - Mol Pharmacol SP - 610 LP - 618 DO - 10.1124/mol.64.3.610 VL - 64 IS - 3 AU - Yasuo Imai AU - Sakiyo Asada AU - Satomi Tsukahara AU - Etsuko Ishikawa AU - Takashi Tsuruo AU - Yoshikazu Sugimoto Y1 - 2003/09/01 UR - http://molpharm.aspetjournals.org/content/64/3/610.abstract N2 - Breast cancer resistance protein (BCRP), an ATP-binding cassette transporter, confers resistance to a series of anticancer reagents such as mitoxantrone, 7-ethyl-10-hydroxycamptothecin, and topotecan. We reported previously that estrone and 17β-estradiol reverse BCRP-mediated multidrug resistance. In the present study, we demonstrate that BCRP exports estrogen metabolites. First, we generated BCRP-transduced LLC-PK1 (LLC/BCRP) cells, in which exogenous BCRP is expressed in the apical membrane, and investigated transcellular transport of 3H-labeled compounds using cells plated on microporous filter membranes. The basal-to-apical transport (excretion) of mitoxantrone, estrone, and 17β-estradiol was greater in LLC/BCRP cells than in LLC-PK1 cells. Thin-layer chromatography of transported steroids revealed that the transport of estrone and 17β-estradiol was independent of BCRP expression. Alternatively, increased excretion of estrone sulfate and 17β-estradiol sulfate was observed in LLC/BCRP cells. BCRP inhibitors completely inhibited the increased excretion of sulfated estrogens across the apical membrane. Conversion of estrogens into their sulfate conjugates was similar between LLC/BCRP and LLC-PK1 cells, suggesting that the increased excretion of estrogen sulfates was attributable to BCRP-mediated transport. Next, the uptake of 3H-labeled compounds in membrane vesicles from BCRP-transduced K562 (K562/BCRP) cells was investigated. 3H-labeled estrone sulfate, but not 3H-labeled estrone or 17β-estradiol, was taken up by membrane vesicles from K562/BCRP cells, and this was ATP-dependent. Additionally, BCRP inhibitors suppressed the transport of estrone sulfate in membrane vesicles from K562/BCRP cells. These results suggest that BCRP does not transport either free estrone or 17β-estradiol but exports sulfate conjugates of these estrogens. ER -