Nitrogen Substituent Polarity Influences Dithiocarbamate-Mediated Lipid Oxidation, Nerve Copper Accumulation, and Myelin Injury

Abstract

Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate’s nitrogen substituents influences the lipophilicity of the copper complexes it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generate dithiocarbamate-copper complexes that are lipid and water soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined and the quantity of protein carbonyls measured to assess levels of oxidative stress and injury. The data provide evidence that dithiocarbamate-copper complexes are redox active; and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid soluble copper complex, significant increases in copper accumulation, oxidative stress and myelin injury were produced by N,N-diethyldithiocarbamate but not by sarcosine dithiocarbamate.

The significance of copper chelators in clinical and experimental application

“…There are various dithiocarbamates that have been exploited in the last decade for the studies of metal ion uptake and apoptosis in a variety of cells [81][82][83][84][85][86][87]. Strong evidence indicates that the pharmacological and toxicological effects of dithiocarbamates are derived from the formation of complexes between dithiocarbamates and copper [81,82].…”

“…The polarity of dithiocarbamate's nitrogen substitute influences the lipophilicity of the copper complexes. The lipophilicity potentially determines the ability for copper-dithiocarbamate complex to promote copper accumulation in target tissue and induce the toxicological effect [87,88]. particular property of interdependence in their coordination geometry and their redox activity.…”

Linking protein oxidation to environmental pollutants: Redox proteomic approaches

“…Higher protein carbonyls levels were found, for instance, in corkwing wrasse (Symphodus melops) captured near a disused copper mine where water and sediments are contaminated with heavy metals [44]. Also, copper accumulation and oxidative damage have been linked to toxicity of dithiocarbamate fungicides in rats [45,46].…”

Dithiocarbamate Toxicity - An Appraisal

“…DTC metal complexes induce dopamine oxidation and produce intraneuronal oxidative stress leading to neuronal damage (Fitsanakis et al, 2002). Since DTC chelate heavy metals such as Cu, Zn, and Fe, leading to their intraneuronal accumulations, these metals have been implicated in promoting lipid peroxidation, oxidative stress, and enzyme inhibitions causing neurotoxic effects (Nobel et al, 1995;Valentine et al, 2009;Viquez et al, 2009;Viola-Rhenals et al, 2007). Increased production of reactive oxygen species by the actions of mancozeb and zineb is also implicated in their neuronal toxicities (Domico et al, 2007).…”