title: 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 that 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 generated dithiocarbamate-copper complexes that were 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 was measured to assess levels of oxidative stress and injury. The data provided 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.
authors.affiliation: Department of Pathology, Center in Molecular Toxicology, and Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561, USA.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Valentine
authors.forename: Olga M
authors.initials: OM
authors.lastname: Viquez
authors.forename: Kalyani
authors.initials: K
authors.lastname: Amarnath
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.forename: Justin
authors.initials: J
authors.lastname: Zyskowski
authors.forename: Endalkachew N
authors.initials: EN
authors.lastname: Kassa
authors.forename: William M
authors.initials: WM
authors.lastname: Valentine
mesh_terms: D000818:Animals; D003300:Copper / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004050:Ditiocarb / Q000008:administration & dosage / Q000633:toxicity*; D005028:Ethylenebis(dithiocarbamates) / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D013058:Mass Spectrometry; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D009584:Nitrogen / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012521:Sarcosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D013859:Thiocarbamates / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D005028:Ethylenebis(dithiocarbamates); D013859:Thiocarbamates; C055171:sarcosine dithiocarbamate; D008315:Malondialdehyde; D003300:Copper; D004050:Ditiocarb; D009584:Nitrogen; D012521:Sarcosine