The increase in brain iron associated with several neurodegenerative diseases may lead to an increased production of free radicals via the Fenton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6‐hydroxydopamine (6‐OHDA) releases iron from the ferritin core by reducing it to the ferrous form. Iron release induced by 6‐OHDA and structurally related compounds and two other dopaminergic neurotoxins, 1‐methyl‐4‐phenylpyridinium iodide (MPP+) and 1‐trichloromethyl‐1,2,3,4‐tetrahydro‐β‐carboline (TaClo), were compared, to identify the structural characteristics important for such release. 1,2,4‐Trihydroxybenzene (THB) was most effective in releasing ferritin‐bound iron, followed by 6‐OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP+, and TaClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potential and an ortho‐dihydroxyphenyl structure are important in the mechanism by which ferritin iron is mobilized. In the presence of ferritin, both 6‐OHDA and THB strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These results suggest that ferritin iron release contributes to free radical‐induced cell damage in vivo.

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