Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake.
HEK293T cells overexpressing divalent metal transporter-1 (DMT1) were established to screen for small-molecule inhibitors of iron uptake. Using a fluorescence-based assay, we tested 2000 known bioactive compounds to find 3 small molecules that potently block ferrous iron uptake. One of the inhibitors, ebselen, is a seleno compound used in clinical trials as a protective agent against ischemic stroke. Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 microM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake. An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 microM). Both ebselen and PDTC increased cellular levels of reduced glutathione. These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition.
Wetli
Herbert A
HA
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Buckett
Peter D
PD
Wessling-Resnick
Marianne
M
D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001393:Azoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005290:Ferric Compounds / Q000378:metabolism; D005296:Ferrous Compounds / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D017136:Ion Transport / Q000187:drug effects; D054833:Isoindoles; D008345:Manganese / Q000378:metabolism; D016566:Organoselenium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection; D000099236:Solute Carrier Family 11, Member 2
D000975:Antioxidants; D001393:Azoles; D027682:Cation Transport Proteins; D005290:Ferric Compounds; D005296:Ferrous Compounds; D005452:Fluoresceins; D054833:Isoindoles; D008345:Manganese; D016566:Organoselenium Compounds; D011392:Proline; D013859:Thiocarbamates; D000099236:Solute Carrier Family 11, Member 2; C066229:prolinedithiocarbamate; C042986:ebselen; C007740:fluorexon