Formation of DNA adducts and oxidative base damage by copper mediated oxidation of dopamine and 6-hydroxydopamine.
We have investigated the formation of DNA adducts and oxidative base damage produced by copper sulfate activation of dopamine and 6-hydroxydopamine. In the presence of 10 microM copper sulfate both 100 microM dopamine and 100 microM 6-hydroxydopamine formed three similar DNA adducts with 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 produced by these incubations were 5.2 +/- 0.03, 32.6 +/- 2.4, and 0.01 pmol/microg DNA for dopamine, 6-hydroxydopamine, and control incubations, respectively, representing a 520- to 3260-fold increase in the level of this base oxidation product. The use of specific chelators and catalase demonstrated that the reduction of Cu2+ to Cu1+ and the formation of a peroxide plays an important role in the activation of dopamine and 6-hydroxydopamine to form adducts and oxidative base damage. Our results suggest that the oxidation of dopamine by transition metals present in the brain may lead to the formation of both DNA adducts and oxidative base damage in dopaminergic cells. We propose that these processes may contribute to the observed loss of dopaminergic neurons in patients with Parkinson's disease.
Lévay
G
G
Brain Tumor Research Center of the Department of Neurological Surgery, University of California, San Francisco, 94143-0806, USA.
Ye
Q
Q
Bodell
W J
WJ
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D008670:Metals; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000378:metabolism*
D002614:Chelating Agents; D018736:DNA Adducts; D016166:Free Radical Scavengers; D008670:Metals; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016627:Oxidopamine; D003849:Deoxyguanosine; D004298:Dopamine