FORMATION OF DNA-ADDUCTS AND OXIDATIVE BASE DAMAGE BY COPPER MEDIATEDOXIDATION OF DOPAMINE AND 6-HYDROXYDOPAMINE

We have investigated the formation of DNA adducts and oxidative base d amage produced by copper sulfate activation of dopamine and 6-hydroxyd opamine. In the presence of 10 mu M copper sulfate both 100 mu M dopam ine and 100 mu M 6-hydroxydopamine formed three similar DNA adducts wi th relative adduct levels of 8.36 +/- 2.23 x 10(-8) and 7.98 +/- 2.53 x 10(-8), respectively, The levels of 8-hydroxy-2'-deoxyguanosine prod uced by these incubations were 5.2 +/- 0.03, 32.6 +/- 2.4, and 0.01 pm ol/mu g DNA for dopamine, 6-hydroxydopamine, and control incubations, respectively, representing a 520- to 3260-foId increase in the level o f this base oxidation product. The use of specific chelators and catal ase demonstrated that the reduction of Cu2+ to Cu1+ and the formation of a peroxide plays all important role in the activation of dopamine a nd 6-hydroxydopamine to form adducts and oxidative base damage. Our re sults suggest that the oxidation of dopamine by transition metals pres ent in the brain may lead to the formation of both DNA adducts and oxi dative bass damage in dopaminergic cells. We propose that these proces ses may contribute to the observed loss of dopaminergic neurons in pat ients with Parkinson's disease. (C) 1997 Academic Press.