Pro-oxidant DNA Breakage Induced by the Interaction of L-DOPA with Cu(II): A Putative Mechanism of Neurotoxicity

Abstract

There are reports in scientific literature that the concentration of copper ions in Parkinsonian brain is at a level that could promote oxidative DNA damage. The possibility of copper chelation by antioxidants excited us to explore the generation of reactive oxygen species (ROS) and DNA damage by the interaction of L-DOPA with Cu(II) ions. In the present manuscript, L-DOPA was tested for its ability to bind with Cu(II) and reduce it to Cu(I). The generation of ROS, such as superoxide anion (O(2)(-)) and hydroxyl radical (OH(•)), was also ascertained. As a result of L-DOPA and Cu(II) interaction, the generation of O(2)(-) was found to be increased in a time-dependent manner. Moreover, the formation of OH(•) was also found to be enhanced with increasing concentrations of L-DOPA. Furthermore, Comet assay results clearly showed significantly higher cellular DNA breakage in lymphocytes treated with L-DOPA and Cu(II) as compared to those that were treated with L-DOPA alone. However, such DNA degradation was inhibited to a significant extent by scavengers of ROS and neocuproine, a membrane permeable Cu(I)-specific sequestering agent. These findings demonstrate that L-DOPA exhibits a pro-oxidant activity in the presence of copper ions.

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

“…Some reports have implied that L-DOPA may accelerate the deterioration of Parkinsonian patients, and that L-DOPA toxicity occurs in damaged dopaminergic neurons in vivo (Ogawa et al, 1994; Blunt et al, 1993; Walkinshaw et al, 1995). It is noteworthy that L-DOPA production from tyrosine is mediated by a copper containing enzyme, tyrosine hydroxylase, presenting the possibility of copper chelation (Perveen et al, 2014). …”

cis-Bis(L-DOPA-κ2 N,O)copper(II) monohydrate: synthesis, crystal structure, and approaches to the analysis of pseudosymmetry

“…An understanding of the prevalence of the unusual packing of CuLD would be enhanced by a crystallographic study of the related crystalline racemic complex (Kwik et al, 1974). Additionally, as mentioned earlier, it is evident that Cu II has a relationship to PD in certain areas, including a proposed mechanism for neurotoxicity via pro-oxidant DNA breakage (Perveen et al, 2015) and the use of Cu II in metal chelation therapy of PD (Tosato & Di Marco, 2019), as well as the pathogenic aspects of Cu II and other metal ions in PD through their relation with -synuclein (Cole et al, 2005;Barnham & Bush, 2008). We believe that the present and further structural studies of l-DOPA complexes will aid in developing an understanding of the role of Cu II and other metals in PD.…”

“…After certain difficulties with data quality were overcome, we carried out a successful X-ray structure determination, with an initial view to elucidating the coordination environment and determining which N,O-isomer was obtained. Additionally, the current interest in Cu II together with l-DOPA in a proposed mechanism for neurotoxicity via pro-oxidant DNA breakage (Perveen et al, 2015), as well as the use of Cu II in metal-chelation therapy of PD (Tosato & Di Marco, 2019), suggested to us that structural information on copper(II) l-DOPA species might be helpful and valuable.…”

An insight towards anticancer potential of major coffee constituents

“…Data from the above literature suggest that coffee components, mainly the caffeine, caffeic acid, cafestol, and kahweol, have anti‐genotoxic and nonmutagenic potentials. It should be mentioned here that substances having antioxidant property may act as cell protective agents at low concentrations while at higher concentration, they could act as a pro‐oxidants . The possible cellular mechanism by which coffee components could influence genotoxicity has been depicted in Fig.…”