title: Membrane transport of dietary phenethyl isothiocyanate by ABCG2 (breast cancer resistance protein).
abstract: Isothiocyanates (ITCs) are non-nutrient constituents abundant in cruciferous vegetables and are effective in blocking carcinogenesis in a variety of tissues. ITCs permeate into cells rapidly and accumulate in cells primarily as glutathione (GSH) conjugates. We have demonstrated recently that certain ITCs are inhibitors of ABCG2 (breast cancer resistance protein, BCRP), an ATP-binding cassette transporter that plays an important role in drug absorption and disposition as well as in the development of multidrug resistance in cancer cells. The purpose of this study was to investigate the mechanisms of interactions between ITCs and BCRP and elucidate the transport of phenethyl isothiocyanate (PEITC) by BCRP. Inside-out membrane vesicles were prepared from human breast cancer BCRP-overexpressing MCF-7/MX100 and the parental MCF-7/sensitive cells. The ATPase study using 100 muM ITCs showed that ITCs are potential inhibitors of BCRP ATPase activity. The transport of (14)C-PEITC into BCRP-overexpressing MCF-7/MX100 cell vesicles was ATP-dependent and inhibited by fumitremorgin C (FTC), a specific inhibitor of BCRP, indicating that PEITC is a substrate for BCRP. In the control MCF-7/sensitive cell vesicles, no ATP-dependent and FTC-inhibited transport of (14)C-PEITC was observed. Taken together, the results of this investigation provided evidence that ITCs are potential inhibitors of BCRP ATPase and PEITC, in its unchanged form, is transported by BCRP. These data may be important in elucidating the interaction of ITCs and cellular transporters and in understanding the potential food-drug interaction.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York at Buffalo, Amherst, New York 14260, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ji
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004032:Diet; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism*; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017879:Isothiocyanates; D009363:Neoplasm Proteins; C058305:phenethyl isothiocyanate; D000251:Adenosine Triphosphatases