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 K_m value for [³H]E₁S was determined to be 16.6 μm. 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 (K_m = 12.9 μm) and [³⁵S]6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate (K_m = 26.9 μM) were also transported by ABCG2. Although [³H]methotrexate, [³H]17β-estradiol-17β-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.