title: Quantitative evaluation of isothiocyanates as substrates and inhibitors of P-glycoprotein.
abstract: The ATP-binding cassette transporter P-glycoprotein (P-gp) exerts a critical role in the systemic disposition of, and exposure to, lipophilic and amphipathic drugs, carcinogens, toxins and other xenobiotics. The ability of P-gp to transfer a wide variety of structurally unrelated compounds from the cell interior across the membrane bilayer remains intriguing. Since dietary chemicals in cruciferous and several other foods appear to exert anticarcinogenic effects by inducing phase II enzymes and inhibiting some phase I enzymes, the isothiocyanate constituents are frequently studied for interactions with various biomacromolecules as well as cytotoxins or isolated cells. Several prominent dietary isothiocyanates were characterized for their interaction with P-gp and their specific effects on the P-gp export activity of several marker substrates. Some of these compounds inhibit the active P-gp-mediated efflux of the fluorescent markers LDS-751 and daunorubicin with low potency, with the most potent among them, phenethyl isothiocyanate, inhibiting transport of the LDS-751 substrate with an IC(50) of approximately 240 microM. Overall, these isothiocyanates are unlikely to impede the xenobiotic defence function of P-gp even in the intestine where the concentrations are potentially high.
authors: Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, NJ 07848, USA.
authors: Mary
authors: M
authors: Barecki-Roach
authors: Er-jia
authors: EJ
authors: Wang
authors: William W
authors: WW
authors: Johnson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D020128:Inhibitory Concentration 50; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D041681:NIH 3T3 Cells; D009930:Organic Chemicals / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D009930:Organic Chemicals; C057718:6-(Dimethylamino)-2-((1E,3E)-4-(4-(dimethylamino)phenyl)-1,3-butadien-1-yl)-1-ethylquinolinium perchlorate; C058305:phenethyl isothiocyanate; D000255:Adenosine Triphosphate; D003630:Daunorubicin