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Carcinogenesis

Iron bound to the lipophilic iron chelator, 8-hydroxyquinoline, causes DNA strand breakage in cultured lung cells.


PMID 8631142

Abstract

The formation of DNA-strand breaks was studied in cultured human lung cells (A 549) subjected to iron, either in the form of iron(III) citrate or in combination with the metal chelators ethylene diamine tetra-acetic acid (EDTA), nitrilo triacetic acid (NTA), or 8-hydroxyquinoline (8HQ). After 15 min exposure to 5 microM iron(III) citrate or iron chelate, the cellular levels of iron were found to be three times higher in cells subjected to iron-8HQ than in cells subjected to iron(III) citrate, iron-EDTA or iron-NTA. Exposure to iron-8HQ caused extensive DNA-strand breakage, whereas no such breakage was found in cells exposed to iron-EDTA or iron-NTA. The DNA damage caused by iron-8HQ increased with time and dose, and DNA-strand breakage was clearly demonstrable in cells after 15 min exposure to as little as 0.1 microM iron-8HQ. Moreover, iron-8HQ was strongly toxic to the cells and inhibited their growth after exposure. Along with the formation of DNA-strand breaks, the concentration of cellular malondialdehyde increased four-fold after exposure to iron-8HQ and two-fold after exposure to iron-EDTA or iron-NTA, suggesting that reactive oxygen metabolites might be involved in the toxic action. Moreover, both iron-EDTA and iron-NTA caused a considerable hydroxylation of deoxyguanosine (dG) residues in DNA in vitro, whereas iron(III) citrate and iron-8HQ only caused a minor hydroxylation of dG. This points to the possibility that iron-8HQ-mediated DNA-strand breakage in cells might be due to the action of a metal-bound oxyl radical formed from the iron-8HQ complex rather than to the formation of hydroxyl radicals. Altogether, these findings indicate that iron bound to the lipophilic chelator, 8HQ, has strong toxic properties and that it may cause substantial DNA-strand breakage and lipid peroxidation in living cells.

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