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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 ?H2AX in cancer cell lines accumulating high copper. Immunofluorescence demonstrated the co-localization of downstream repair factor 53BP1 at the damaged induced ?H2AX 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.

SUBMITTER: Rehmani N

PROVIDER: S-EPMC5404347 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Rehmani Nida N Zafar Atif A Arif Hussain H Hadi Sheikh Mumtaz SM Wani Altaf A AA

Toxicology in vitro : an international journal published in association with BIBRA 20170128

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 mo ...[more]

PMID: 28137434

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Project description:BackgroundPurpurin (1,2,4-trihydroxy-9,10-anthraquinone), a natural red anthraquinone pigment, has historically been used as a textile dye. However, purpurin induced urinary bladder tumors in rats, and displayed a mutagenic activity in assay using bacteria and mammalian cells. Many carcinogenic dyes are known to induce bladder cancers via DNA adduct formation, but carcinogenic mechanisms of purpurin remain unknown. In this study, to clarify the mechanism underlying carcinogenicity of purpurin, copper-mediated DNA damage induced by purpurin was examined using 32P-labeled DNA fragments of human genes relevant to cancer. Furthermore, we also measured 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an indicator of oxidative DNA damage, in calf thymus DNA.ResultsPurpurin plus Cu(II) cleaved 32P-labeled DNA fragments only under piperidine treatment, indicating that purpurin caused base modification, but not breakage of the DNA backbone. In the absence of Cu(II), purpurin did not induce DNA cleavage even with piperidine treatment. Purpurin plus Cu(II) caused piperidine-labile sites predominantly at G and some T residues. Bathocuproine, a Cu(I) chelator, completely prevented the occurrence of piperidine-labile sites, indicating a critical role of Cu(I) in piperidine-labile sites induced by purpurin plus Cu(II). On the other hand, methional, a scavenger of a variety of reactive oxygen species (ROS) and catalase showed limited inhibitory effects on the induction of piperidine-labile sites, suggesting that ROS could not be major mediators of the purpurin-induced DNA damage. Considering reported DNA adduct formation by quinone metabolites of several carcinogenic agents, quinone form of purpurin, which is possibly generated via purpurin autoxidation accompanied by Cu(I)/Cu(II) redox cycle, might lead to DNA adducts and piperidine-labile sites. In addition, we measured contents of 8-oxodG. Purpurin moderately but significantly increased 8-oxodG in calf thymus DNA in the presence of Cu(II). The 8-oxodG formation was inhibited by catalase, methional and bathocuproine, suggesting that Cu(I)-hydroperoxide, which was generated via Cu(I) and H2O2, caused oxidative DNA base damage.ConclusionsWe demonstrated that purpurin induces DNA base damage possibly mediated by Cu(I)/Cu(II) redox cycle both with and without ROS generation, which are likely to play an important role in its carcinogenicity.

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

Publications

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

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