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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Depletion of mitochondrial coenzyme A and glutathione by 4-dimethylaminophenol and formation of mixed thioethers.

4-Dimethylaminophenol (DMAP), an antidote in cyanide poisoning, has been shown to produce kidney lesions in rats, to damage isolated rat kidney tubules and to impair mitochondrial functions as already described for 4-aminophenol. Since DMAP upon oxidation forms bis- and tris-substituted thioethers with GSH, it was anticipated that mitochondrial toxicity of DMAP might result from CoA depletion. In a model reaction DMAP was oxidized by oxyhemoglobin in the presence of CoA and GSH resulting in formation of tris-(CoA-S-yl)-DMAP, tris-(GSH-S-yl)-DMAP and two mixed thioethers, namely, (CoA-S-yl)-bis-(GSH-S-yl)-DMAP and (GSH-S-yl)-bis-(CoA-S-yl)-DMAP. The compounds were isolated by HPLC and identified spectroscopically, by amino acid analysis and Raney-Nickel desulfuration. Rat liver mitochondria (5 mg protein/ml) incubated under state IV conditions with 20 and 50 microM DMAP were depleted of GSH and total coenzyme A with formation of GSSG and the above-mentioned thioethers which were quantified by isotope dilution techniques using [14C]-labelled DMAP and the isolated, inactive thioethers. The results confirm earlier suggestions that part of the cytotoxicity of DMAP may result from depletion of vital mitochondrial thiols, particularly CoA. Since 4-aminophenol reacts analogously, similar cytotoxic effects can be expected from compounds which on (aut)oxidation form quinoid systems capable of 1.4-addition reactions with nucleophilic thiols.[1]


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