Organ Toxicity and Metabolic Pathway of 4-Dimethylaminophenol

  • R. Elbers
  • P. Eyer
  • H. Kampffmeyer
  • S. Soboll
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


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.


Organ Toxicity Phenoxyl Radical Cyanide Poisoning Reactive Thiol Mixed Function Oxidase System 
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  1. 1.
    R.Nery, Some new aspects of the metabolism of phenacetin in the rat, Biochem.J. 122, 317–326 (1971)PubMedGoogle Scholar
  2. 2.
    J.R.Mitchell, W.Z.Potter, J.A.Hinson, W.R.Snodgrass, J.A.Timbrell, and J.R.Gillette, Toxic drug reactions, Handb.exp.Pharm. 28/3, 383–419 (1975)Google Scholar
  3. 3.
    J.R.Gillette, J.A.Hinson, G.Mulder, L.R.Pohl, S.D.Nelson, and J.R.Mitchell, Reactive metabolites of phenacetin and acetaminophen, This issue (1980)Google Scholar
  4. 4.
    M.Kiese and N.Weger, Formation of ferrihaemoglobin with aminophenols in the human for the treatment of cyanide poisoning, Europ.J.Pharmacol. 7, 97–105 (1969)CrossRefGoogle Scholar
  5. 5.
    D.Christel, P.Eyer, M.Hegemann, M.Kiese, W.Lörcher, and N.Weger, Pharmacokinetics of cyanide in poisoning of dogs and the effect of 4-dimethylaminophenol or thiosulfate, Arch.Toxicol. 38, 177–189 (1977)PubMedCrossRefGoogle Scholar
  6. 6.
    R.Klimmek, H.Fladerer, and N.Weger, Circulation, respiration and blood homeostasis in cyanide-poisoned dogs after treatment with 4-dimethylaminophenol or cobalt compounds, Arch.Toxicol. 43, 121–133 (1979)PubMedCrossRefGoogle Scholar
  7. 7.
    Symposium on paracetamol and the liver, J.Int.Med. Res.Suppl. 4, 1 (1976)Google Scholar
  8. 8.
    I.C.Calder, C.C.Funder, C.R.Green, K.N.Ham, J.D.Tange, Comparative nephrotoxicity of aspirin and phenacetin derivatives, IV, 518–521 (1971)Google Scholar
  9. 9.
    C.A.Crowe, I.C.Calder, N.P.Madsen, C.C.Funder, C.R.Green, K.N.Ham, J.D.Tange, An experimental model of analgesic-induced renal damage–Some effects of p-aminophenol on rat kidney mitochondria, Xenobiotica 7, 345–356 (1977)PubMedCrossRefGoogle Scholar
  10. 10.
    P.Eyer, M.Kiese, G.Lipowsky, and N.Weger, Reactions of 4-dimethylaminophenol with hemoglobin, and auto-oxidation of 4-dimethylaminophenol, Chem.Biol.Interact. 8, 41–59 (1974)PubMedCrossRefGoogle Scholar
  11. 11.
    L.Szinicz, N.Weger, W.Schneiderhan, and M.Kiese, Nephrotoxicity of aminophenols: Effects of 4-dimethylaminophenol on isolated rat kidney tubules, Arch.Toxicol. 42, 63–73 (1979)PubMedCrossRefGoogle Scholar
  12. 12.
    St.Steenken, E.Lengfelder, and P.Eyer, Unpublished results, Munich (197913. H.Sies, Ch.Gerstenecker, H.Menzel, and L.Flohé, Oxidation in the NADP system and release of GSSG from hemoglobin-free perfused rat liver during peroxidatic oxidation of glutathione by hydroperoxides, FEBS letters 27, 171 (1972)CrossRefGoogle Scholar
  13. 14.
    P.Eyer and M.Kiese, Biotransformation of 4-dimethylaminophenol: Reaction with glutathione,and some properties of the reaction products, Chem.Biol.Interact. 14, 165–178 (1976)PubMedCrossRefGoogle Scholar
  14. 15.
    P.Eyer, Industrial and environmental xenobiotics (Eds.J.R.Fouts und J.Gut), Excerpta medica 290 AM (1978)Google Scholar
  15. 16.
    L.Szinicz and R.Elbers, Interactions of 4-dimethylaminophenol (DMAP) with Coenzyme A (CoA), NaunynSchmiedeberg’s Arch.Pharmacol., in press (1980)Google Scholar
  16. 17.
    P.Eyer and H.Gaber, Biotransformation of 4-dimethylaminophenol in the dog, Biochem.Pharmacol. 27, 2215–2221 (1978)PubMedCrossRefGoogle Scholar
  17. 18.
    R.Elbers, H.G.Kampffmeyer, and H.Rabes, Effects and metabolic pathway of 4-dimethylaminophenol during kidney perfusion, Xenobiotica, in press (1980)Google Scholar
  18. 19.
    P.Jancso, über die Biotransformation von 4-Dimethylaminophenol im Menschen, Thesis, Munich(1980)Google Scholar
  19. 20.
    M.Kiese, L.Szinicz, N.Thiel, and N.Weger, Ferrihemoglobin and kidney lesions in rats produced by 4-aminophenol and DMAP, Arch.Toxicol. 34, 337–339 (1975)PubMedCrossRefGoogle Scholar
  20. 21.
    P.Eyer and H.G.Kampffmeyer, Biotransformation of 4-dimethylaminophenol in the isolated perfused rat liver and in the rat, Biochem.Pharmac. 27, 2223–2228 (1978)CrossRefGoogle Scholar
  21. 22.
    L.Szinicz and N.Weger, Effects of 4-dimethylaminophenol in rat kidneys, isolated rat kidney tubules and hepatocytes, Xenobiotica, in press (1980)Google Scholar
  22. 23.
    R.Elbers, S.Soboll, and H.G.Kampffmeyer, Alterations in cellular intermediary metabolism by 4-dimethylaminophenol in the isolated perfused rat liver and the implications for 4-dimethylaminophenol toxicity, Biochem.Pharmacol. 29, 1747–1753 (1980)PubMedCrossRefGoogle Scholar
  23. 24.
    A.Wahlländer, S.Soboll, and H.Sies, Hepatic,mitochondrial and cytosolic glutathione content and the sub-cellular distribution of GSH-transferase, FEBS Lett. 97, 138–140 (1979)Google Scholar
  24. 25.
    S.Soboll, R.Scholz, M.Freisel, R.Elbers, and H.W.Heldt, Distribution of metabolites between mitochondria and cytosol of perfused liver, in “Use of Isolated Liver Cells and Kidney Tubules in Metabolic Studies” (J.M.Tager, H.D.Söling, and J.R.Williamson eds.) Academic Press, New York and London, 29–40 (1976)Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • R. Elbers
    • 1
  • P. Eyer
    • 1
  • H. Kampffmeyer
    • 1
  • S. Soboll
    • 2
  1. 1.Institut für Pharmakologie und ToxikologieUniversität MünchenMünchen 2Germany
  2. 2.Institut für Physiologische Chemie IUniversität DüsseldorfGermany

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