Inhibition of the 26S proteasome as a possible mechanism for toxicity of heavy metal species

• A correlation is investigated between heavy metal complexes and proteasomal activity.
• Aluminum, cadmium, mercury, lead and tin complexes were tested.
• The toxicity of the aluminum and tin species cannot be associated to the proteasome.
• The toxicity of cadmium and lead are potentially associated with proteasome inhibition.
• The relationship between the mercury species and the proteasome is strongly suggested.

In this paper we report on the synthesis of five metal complexes coordinated to the [NN′O] ligand HLiodo (2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol), namely [AlIII(Liodo)2]ClO4 (1), [CdII(Liodo)Cl]·H2O (2), [HgII(Liodo)2]·4DMSO (3), [PbII(Liodo)NO3] (4), and [SnIV(Liodo)Cl3] (5). Species 1–5 are thoroughly characterized by spectroscopic and spectrometric methods, as well as by elemental analysis. X-ray crystallography results for complex 3 indicate the presence of Hg(II) ion hexacoordinated to two facially oriented [NN′O] ligands, whereas for complex 5 an Sn(IV) ion chelates to one deprotonated ligand and three chlorido coligands. The toxicity of species 1–5 is tested against transformed human prostate epithelial cells CRL2221 and we observe that the five complexes demonstrate high levels of cell growth inhibition in a dose-dependent manner. In order to evaluate the relationship between these species and the proteasome, we test 1–5 against purified 20S, CRL2221 cell extracts, and intact cells, followed by the measurement of the percent chymotrypsin-like activity inhibition levels. Results suggest a good correlation between the toxicity of [HgII(Liodo)2]·4DMSO (3) and proteasome inhibition.

The correlation between toxicity of heavy metal ions and proteasomal activity inhibition is investigated. While aluminum and tin complexes do not seem directly linked to the 26S proteasome activity, mercury, cadmium and lead species show chymotrypsin-like activity inhibition in a dose-dependent manner.Figure optionsDownload as PowerPoint slide