title: The permeability and cytotoxicity of insulin-mimetic vanadium (III,IV,V)-dipicolinate complexes.
abstract: Vanadium (III,IV,V)-dipicolinate complexes with different redox properties were selected to investigate the structure-property relationship of insulin-mimetic vanadium complexes for membrane permeability and gastrointestinal (GI) stress-related toxicity using the Caco-2 cell monolayer model. The cytotoxicity of the vanadium complexes was assayed with 3-(4,5-dimethylthiazoyl-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assays and the effect on monolayer integrity was measured by the trans-epithelial electric resistance (TEER). The three vanadium complexes exhibited intermediate membrane permeability (P(app) = 1.4-3.6x10(-6) cm/s) with low cellular accumulation level (<1%). The permeability of all compounds was independent of the concentration of vanadium complexes and excess picolinate ligands. Both V(III) and V(V)-dipicolinate complexes induced 3-4-fold greater reactive oxygen and nitrogen species (RONS) production than the V(IV)-dipicolinate complex; while the vanadium (III)-dipicolinate was 3-fold less damaging to tight junction of the Caco-2 cell monolayer. Despite the differences in apparent permeability, cellular accumulation, and capacity to induce reactive oxygen and nitrogen species (RONS) levels, the three vanadium complexes exhibited similar cytotoxicity (IC50 = 1.7-1.9 mM). An ion pair reagent, tetrabutylammonium, increased the membrane apparent permeability by 4-fold for vanadium (III and IV)-dipicolinate complexes and 16-fold for vanadium (V)-dipicolinate as measured by decrease in TEER values. In addition, the ion pair reagent prevented damage to monolayer integrity. The three vanadium (III,IV,V)-dipicolinate complexes may pass through caco-2 monolayer via a passive diffusion mechanism. Our results suggest that formation of ion pairs may influence compound permeation and significantly reduce the required dose, and hence the GI toxicity of vanadium-dipicolinate complexes.
authors.affiliation: National Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, XueyuanRoad 38, HaiDian District, Beijing 100083, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Da
authors.initials: XD
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Crans
mesh_terms: D018938:Caco-2 Cells; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D009942:Organometallic Compounds / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D010848:Picolinic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology / Q000633:toxicity; D019108:Tight Junctions / Q000378:metabolism; D013997:Time Factors; D017968:Vanadium Compounds / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D007328:Insulin; D009942:Organometallic Compounds; D010848:Picolinic Acids; D013778:Tetrazolium Salts; D013844:Thiazoles; D017968:Vanadium Compounds; C022616:thiazolyl blue; C004860:dipicolinic acid