Copper-mediated DNA damage by the neurotransmitter dopamine and L-DOPA: A pro-oxidant mechanism

• Published in: Toxicology in vitro 2017-04, Vol.40, p.336-346
• Main Authors: Rehmani, Nida, Zafar, Atif, Arif, Hussain, Hadi, Sheikh Mumtaz, Wani, Altaf A.
• Format: Article
• Language: English
• Subjects: Aging; Bioassays; Breakage; Cancer; Catecholamines; Cell Line; Cell Line, Tumor; Chelating Agents - pharmacology; Cleavage; Comet assay; Copper; Copper - chemistry; Copper - pharmacology; Copper compounds; Damage accumulation; Damage detection; Damage localization; Deoxyribonucleic acid; Dihydroxyphenylalanine; DNA; DNA Damage; Dopamine; Dopamine - chemistry; Dopamine - pharmacology; Dopamine Agents - chemistry; Dopamine Agents - pharmacology; Electrophoresis; Gel electrophoresis; Humans; Immunofluorescence; L-DOPA; Levodopa; Levodopa - chemistry; Levodopa - pharmacology; Localization; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Metabolites; Molecular docking; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurotoxicity; Neurotransmitters; Oxidation; Oxidation-Reduction; Pathogenesis; Phenanthrolines - pharmacology; Reactive Oxygen Species - chemistry; Reactive Oxygen Species - pharmacology; Toxicity; Tumor cell lines; γH2AX
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.01.020

Oxidative DNA damage has been implicated in the pathogenesis of neurological disorders, cancer and ageing. Owing to the established link between labile copper concentrations and neurological diseases, it is critical to explore the interactions of neurotransmitters and drug supplements with copper. Herein, we investigate the pro-oxidant DNA damage induced by the interaction of L-DOPA and dopamine (DA) with copper. The DNA binding affinity order of the compounds has been determined by in silico molecular docking. Agarose gel electrophoresis reveals that L-DOPA and DA are able to induce strand scission in plasmid pcDNA3.1 (+/−) in a copper dependent reaction. These metabolites also cause cellular DNA breakage in human lymphocytes by mobilizing endogenous copper, as assessed by comet assay. Further, L-DOPA and DA-mediated DNA breaks were detected by the appearance of post-DNA damage sensitive marker γH2AX in cancer cell lines accumulating high copper. Immunofluorescence demonstrated the co-localization of downstream repair factor 53BP1 at the damaged induced γH2AX foci in cancer cells. The present study corroborates and provides a mechanism to the hypothesis that suggests metal-mediated oxidation of catecholamines contributes to the pathogenesis of neurodegenerative diseases. [Display omitted] •Catecholamines induce significant DNA damage by mobilizing endogenous Cu(II) ions.•L-DOPA and dopamine possess the ability to reduce Cu(II) to Cu(I).•L-DOPA and dopamine induce Cu(II)-mediated foci formation and co-localization of γH2AX & 53BP1 at damage sites.•Owing to its structural differences, L-DOPA is more efficient as a pro-oxidant than dopamine.