title: Copper-mediated DNA damage by the neurotransmitter dopamine and L-DOPA: A pro-oxidant mechanism.
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP 202002, India. Electronic address: nida.rehmani4@gmail.com.
authors.forename: Nida
authors.initials: N
authors.lastname: Rehmani
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP 202002, India. Electronic address: zafaratif35@yahoo.com.
authors.forename: Atif
authors.initials: A
authors.lastname: Zafar
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP 202002, India. Electronic address: arifkap@gmail.com.
authors.forename: Hussain
authors.initials: H
authors.lastname: Arif
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP 202002, India. Electronic address: smhadi1946@gmail.com.
authors.forename: Sheikh Mumtaz
authors.initials: SM
authors.lastname: Hadi
authors.affiliation: Department of Radiology, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA; James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. Electronic address: wani.2@osu.edu.
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Wani
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004249:DNA Damage; D004298:Dopamine / Q000737:chemistry / Q000494:pharmacology*; D015259:Dopamine Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007980:Levodopa / Q000737:chemistry / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D015259:Dopamine Agents; D010618:Phenanthrolines; D017382:Reactive Oxygen Species; D007980:Levodopa; D003300:Copper; C002701:neocuproine; D004298:Dopamine
keywords: Copper; DNA damage; Dopamine; L-DOPA; Neurotoxicity; γH2AX