Combined effects of manganese, iron, copper, and dopamine on oxidative DNA damage

Abstract

Manganese (Mn) damages the central nervous system and causes Parkinson's disease (PD)-like syndrome called manganism. Abnormal accumulationof Mn and iron (Fe) is observed in the basal nuclei of patients with PD. Dopamine induces oxidative DNA damage in the presence of Fe or copper (Cu) in vitro. Therefore, an Mn-induced neural disorder may involve combined actions of Mn, Fe/Cu, and catecholamines. Here we investigated the combined effects of Mn(II) on the DNA damage induced by dopamine and either Fe(III) or Cu(II). Mn(II) enhanced the formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) induced by dopamine and Fe(III)/Cu(II), whereas Mn(II) did not induce 8-oxodG formation in the absence of Fe(III)/Cu(II). Mn(II) accelerated hydrogen peroxide (H2O2) production in the dopamine-Fe(III)/Cu(II) system. Furthermore, Mn(II) decreased superoxide anion radicals (O•2) generated in the xanthine-xanthine oxidase system. These results indicate that Mn(II)-mediated enhancement of DNA damage is caused by facilitated conversion of O•2 to H2O2. In addition, Mn(II) accelerated the formation of aminochrome, an oxidized dopamine product, in the presence of Cu(II). This reaction may have involved Mn(III) accompanied by H2O2 production from OO•2, suggesting a mechanism for Mn-induced oxidative stress on dopaminergic neurons through the combined actions of Mn, Fe, Cu, and dopamine. © 2011 The Pharmaceutical Society of Japan.