Carbamoylation of brain glutamate receptors by a disulfiram metabolite.
S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), a metabolite of the drug disulfiram, is a selective carbamoylating agent for sulfhydryl groups. Treatment of glutamate receptors isolated from mouse brain with DETC-MeSO blocks glutamate binding. In vivo, carbamoylated glutathione, administered directly to mice or formed by reaction of DETC-MeSO with glutathione in the blood, also blocks brain glutamate receptors. Carbamoyl groups appear to be delivered to brain glutamate receptors or to liver aldehyde dehydrogenase in vivo by a novel glutathione-mediated mechanism. Seizures caused by the glutamate analogs N-methyl-D-aspartate and methionine sulfoximine, or by hyperbaric oxygen, are prevented by DETC-MeSO, indicating that carbamoylation of glutamate receptors gives an antagonist effect. These observations offer an explanation for some of the previously reported neurological effects of disulfiram, such as its ability to prevent O2-induced seizures. Furthermore, some of the physiology of the disulfiram-ethanol reaction, that could not be accounted for based on the known inhibition of aldehyde dehydrogenase alone, may be explained by disulfiram's effect on glutamate receptors.
Nagendra
S N
SN
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA.
Faiman
M D
MD
Davis
K
K
Wu
J Y
JY
Newby
X
X
Schloss
J V
JV
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D004221:Disulfiram / Q000378:metabolism* / Q000494:pharmacology; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006931:Hyperbaric Oxygenation; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; D004050:Ditiocarb; D004221:Disulfiram