Organ Toxicity and Metabolic Pathway of 4-Dimethylaminophenol
Toxication of xenobiotics by intracellular activation to potent alkylating or arylating agents has been observed in several classes of drugs. For N-acetamidophenols, transformation into reactive intermediates by a cytochrome P-450 mixed function oxidase leading, hypothetically via N-hydroxy derivatives, to the assumed ultimate toxic compound N-acetylbenzoquinonimine has been proposed by Nery 1 and extended by Gillette and Mitchell 2, 3. In this laboratory the biotransformation and toxicity of 4-dimethylaminophenol (DMAP), an antidote used in cyanide poisoning4–6,has been studied in vivo, in isolated cells, and in vitro. Since toxicity of N-acetamidophenols aminophenols is manifested by damage to liver7 and/or kidney8, 9, we extended investigations on the biotransformation of DMAP to the alterations of cellular intermediary metabolism in isolated perfused rat liver and kidney. This communication summarizes some of our findings on the mechanism of DMAP-toxicity which could be similar to other 4-aminophenols capable to form a p-quinonimine structure.
KeywordsOrgan Toxicity Phenoxyl Radical Cyanide Poisoning Reactive Thiol Mixed Function Oxidase System
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