title: The effect of hexaaza- and hexathia-macrocyclic ligands on transition metal cytotoxicity in human hepatoma-derived cultured cells.
abstract: The effect of macrocyclic ligands on cytotoxic concentrations of the transition metal ions of copper, zinc, and cadmium was investigated. For this purpose, a hexaaza- [3,6,9,17,20,23-hexaazatricyclo[23.3.1.1(11,15)] triaconta-1(29),11(30),12,14,25,27-hexaene (L2)] and hexathia-chelating ligand [1,4,7,10,13,16-hexathiacyclooctadecane (L3)] were used in the human hepatoma-derived HepG2 cell line. The cytotoxicity was measured by the neutral red uptake inhibition assay. First, the NI50 of the ligands, i.e., the concentration of the ligand inducing a 50% inhibition in neutral red uptake compared to control cells, was determined. In several metal/ligand combination experiments, the effects for L2 were difficult to interpret, whereas for L3 in combination with copper ions, a severe increase -- and for zinc ions, a significant decrease of cell toxicity -- relative to the metal control was observed. To further examine the different effects observed with L3 in combination with, respectively, Cu2+ and Zn2+, the glutathione (GSH) content was measured. The relative GSH content decreased as the concentration of L3 increased. It was proposed that the increased toxicity of the combination Cu(2+)/L3 could be caused by the depletion of GSH and a subsequent inability to scavenge the produced reactive oxygen species (ROS). This hypothesis was supported by experiments during which vitamin E or C was added to the Cu(2+)/L3 system.
authors.affiliation: Toxicology Division, Scientific Institute of Public Health, Brussels, Belgium. peter.smet@iph.fgov.be
authors.forename: P W
authors.initials: PW
authors.lastname: Smet
authors.forename: T F
authors.initials: TF
authors.lastname: Pauwels
authors.forename: P J
authors.initials: PJ
authors.lastname: Dierickx
mesh_terms: D000473:Alkanes / Q000494:pharmacology*; D002104:Cadmium / Q000493:pharmacokinetics*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000493:pharmacokinetics*; D005978:Glutathione / Q000032:analysis; D006586:Hexanes / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008113:Liver Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000493:pharmacokinetics*
chemical_list: D000473:Alkanes; D002614:Chelating Agents; D006586:Hexanes; D008024:Ligands; D002104:Cadmium; D003300:Copper; D005978:Glutathione; D015032:Zinc; C012867:decane