ToxSci Advance Access originally published online on June 8, 2004
Toxicological Sciences 2004 81(1):160-171; doi:10.1093/toxsci/kfh190
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Toxicological Sciences vol. 81 no. 1 © Society of Toxicology 2004; all rights reserved.
N,N-Diethyldithiocarbamate Produces Copper Accumulation, Lipid Peroxidation, and Myelin Injury in Rat Peripheral Nerve
* Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561; and Department of Pathology, University of Washington, Seattle, Washington 98104-2499
Received May 7, 2004; accepted June 3, 2004
Previous studies have demonstrated the ability of the dithiocarbamate, disulfiram, to produce a peripheral neuropathy in humans and experimental animals and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a proximate toxic species of disulfiram. The ability of DEDC to elevate copper levels in the brain suggests that it may also elevate levels of copper in peripheral nerve, possibly leading to oxidative stress and lipid peroxidation from redox cycling of copper. The study presented here investigates the potential of DEDC to promote copper accumulation and lipid peroxidation in peripheral nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps and fed a normal diet or diet containing elevated copper, and the levels of metals, isoprostanes, and the severity of lesions in peripheral nerve and brain were assessed by ICP–AES/AAS, GC/MS, and light microscopy, respectively. Copper was the only metal that demonstrated any significant compound-related elevations relative to controls, and total copper was increased in both brain and peripheral nerve in animals administered DEDC on both diets. In contrast, lesions and elevated F2-isoprostanes were significantly increased only in peripheral nerve for the rats administered DEDC on both diets. Autometallography staining of peripheral nerve was consistent with increased metal content along the myelin sheath, but in brain, focal densities were observed, and a periportal distribution occurred in liver. These data are consistent with the peripheral nervous system being more sensitive to DEDC-mediated demyelination and demonstrate the ability of DEDC to elevate copper levels in peripheral nerve. Additionally lipid peroxidation appears to either be a contributing event in the development of demyelination, possibly through an increase of redox active copper, or a consequence of the myelin injury.
Key Words: copper; demyelination; disulfiram; dithiocarbamate; isoprostanes; lipid peroxidation; myelin.
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