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The effect of hexaaza-and hexathia–macrocyclic ligands on transition metal cytotoxicity in human hepatoma-derived cultured cells

Laboratory of Biochemical Toxicology, Toxicology Division, Scientific Institute of Public Health, J. Wytsmanstraat 16, Brussels 1050, Belgium; peter.smet{at}iph.fgov.be

T F Pauwels

Department of General and Inorganic Chemistry, University of Ghent, Krijgslaan 281 (S3), Ghent 9000, Belgium

P J Dierickx

Laboratory of Biochemical Toxicology, Toxicology Division, Scientific Institute of Public Health, J. Wytsmanstraat 16, Brussels 1050, Belgium

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 Cu²⁺ /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 Cu²⁺ / L3 system.

Key Words: cadmium • chelating ligands • copper • GSH • HepG2 • macrocyclic ligands • metal toxicity • oxidative stress • ROS • zinc

Human & Experimental Toxicology, Vol. 21, No. 8, 421-427 (2002)
DOI: 10.1191/0960327102ht277oa


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