title: Mobilization of intracellular iron by analogs of pyridoxal isonicotinoyl hydrazone (PIH) is determined by the membrane permeability of the iron-chelator complexes.
abstract: In the ongoing search for an effective, orally active iron-chelator, the capacity of a series of halogenated analogs of pyridoxal isonicotinoyl hydrazone (PIH) to bind intracellular 59Fe and cause its release from cells was investigated. Reticulocytes labeled with 59Fe(2)-transferrin in which heme synthesis was inhibited by succinylacetone were used as a model of 59Fe mobilization. The kinetics of iron binding were similar for all the chelators tested (half-time of approximately 1 hr), and all bound more than twice as much 59Fe as PIH. The rate of release of the 59Fe-chelator complexes from cells depended upon the structure of the chelators. Ortho-substituted analogs were more effective at mobilizing cellular iron than meta and para isomers, due to a more efficient release of the iron complexes from the cell. The iron-chelator complexes which were released slowly from cells had a high affinity for erythrocyte ghost membranes, indicating the role of membrane permeability in the release mechanism of the complexes. The addition of BSA to the extracellular medium increased the extent of iron release by lipophilic analogs in a concentration-dependent manner, presumably by acting as a sink for the lipophilic complexes. The affinity of BSA for the chelators and their Fe(3+) complexes, determined spectrophotometrically, demonstrated that all chelators and their iron complexes bound BSA with dissociation constants ranging from 7,000 to >500,000 M(-1). Understanding the importance of the rate of release of the iron-chelator complex will direct the search for iron-chelators with improved efficacy.
authors.affiliation: Department of Physiology, McGill University and Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, 3755 Chemin de la Cote-Ste-Catherine, Montreal, Que, H3T 1E2, Canada.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Buss
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Arduini
authors.forename: Prem
authors.initials: P
authors.lastname: Ponka
mesh_terms: D000818:Animals; D001692:Biological Transport; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D012156:Reticulocytes / Q000187:drug effects* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007502:Iron Chelating Agents; D012710:Serum Albumin, Bovine; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid