ABCG2 transports sulfated conjugates of steroids and xenobiotics.
The mechanism for the cellular extrusion of sulfated conjugates is still unknown. In the present study, we investigated whether human wild type ABCG2 transports estrone 3-sulfate (E1S) using membrane vesicles from cDNA-transfected mouse lymphoma cell line (P388 cells). The uptake of [3H]E1S into ABCG2-expressing membrane vesicles was stimulated by ATP, and the Km value for [3H]E1S was determined to be 16.6 microm. The ABCG2-mediated transport of [3H]E1S was potently inhibited by SN-38 and many sulfate conjugates but not by glucuronide and glutathione conjugates or other anionic compounds. Other sulfate conjugates such as [3H]dehydroepiandrosterone sulfate (DHEAS) and [35S]4-methylumbelliferone sulfate (Km = 12.9 microm) and [35S]6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040) sulfate (Km = 26.9 microm) were also transported by ABCG2. Although [3H]methotrexate, [3H]17beta-estradiol-17beta-D-glucuronide, [3H]2,4-dinitrophenyl-S-glutathione, and [14C]4-methylumbelliferone glucuronide were transported by ABCG2, this took place to a much lesser extent compared with [3H]E1S. It was suggested that ABCG2 preferentially transports sulfate conjugates and that E1S and DHEAS are the potential physiological substrates for this transporter.
Suzuki
Michiko
M
School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Suzuki
Hiroshi
H
Sugimoto
Yoshikazu
Y
Sugiyama
Yuichi
Y
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D019314:Dehydroepiandrosterone Sulfate / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007700:Kinetics; D008223:Lymphoma; D051379:Mice; D009363:Neoplasm Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D013256:Steroids / Q000493:pharmacokinetics*; D013464:Sulfuric Acids / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015262:Xenobiotics / Q000493:pharmacokinetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D013256:Steroids; D013464:Sulfuric Acids; D015262:Xenobiotics; D019314:Dehydroepiandrosterone Sulfate