Biotransformation and some effects of 2-dimethylamino-4-(N-methylanilino)-phenol in dogs

  • Harald Gaber
  • Manfred Kiese
  • Gerhard Renner
Article

Summary

2-Dimethylamino-4-(N-methylanilino)-phenol (MP), an active metabolite of N,N-dimethylaniline-N-oxide in the autocatalytic formation of ferrihemoglobin, reacted quickly in dogs after intravenous unjection. A dose of 14C-labeled MP which oxidized 40% of the hemoglobin disappeared from the blood in 20 min. During this period of time MP transferred catalytically electrons from ferrohemoglobin to oxygen, reacted with sulfotransferases to form the sulfuric acid ester, and was covalently bound in blood and other tissues.

In the urine, in addition to the sulfuric acid ester of MP (25%), methylamine, dimethylamine, and N-methylaniline were found. Their amount indicated that most of the MP not esterified with sulfuric acid had lost a nitrogen by hydrolysis of the quinonimine.

The metabolites which were covalently bound in blood and other tissues disappeared slowly, traces of radioactivity being found in blood and urine 7 days after i.v. injection of MP, 15 mg/kg.

The formation of methylamines as well as N-methylaniline from MP in vivo and in blood in vitro proves that the oxidation product of MP, a purple dye, is a resonance hybrid of the two structures 2-dimethylamino-N-methyl-N-phenyl-1,4-benzoquinone-4-imonium and 4-(N-methylanilino)-N,N-dimethyl-1,2-benzoquinone-2-imonium. In addition to ferrihemoglobin MP produced numerous Heinz bodies in red cells and caused hemolytic anemia. After lethal doses necroses in the kidney tubules were found.

Key words

2-Dimethylamino-4-(N-methylanilino)-phenol Ferrihemoglobin Covalent binding Methylamines N-Methylaniline 

Abbreviations used

MP

2-dimethylamino-4-(N-methylanilino)-phenol

MP sulfate

sulfuric acid mono[2-dimethylamino-4(N-methylanilino)-phenyl]ester sodium salt

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References

  1. Calder, I. C., Funder, C. C., Green, C. R., Ham, K. N., Tange, J. D.: Comparative nephrotoxicity of aspirin and phenacetin derivatives. Brit. med. J. 1971 IV, 518–525Google Scholar
  2. Calder, I. C., Williams, P. J., Woods, R. A., Funder, C. C., Green, C. R., Ham, K. N., Tange, J. D.: Nephrotoxicity and molecular structure. Xenobiotica 5, 303–307 (1975)Google Scholar
  3. Evelyn, K. A., Malloy, H. T.: Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. J. biol. Chem. 126, 655–662 (1938)Google Scholar
  4. Eyer, P., Kiese, M., Lipowsky, G., Weger, N.: Metabolism of 4-dimethylaminophenol. Naunyn-Schmiedebergs Arch. Pharmak. 270, R29 (1971)Google Scholar
  5. Eyer, P., Kiese, M., Lipowsky, G., Weger, N.: Reactions of 4-dimethylaminophenol with hemoglobin, and autoxidation of 4-dimethylaminophenol. Chem. biol. Interact. 8, 41–59 (1974)Google Scholar
  6. Eyer, P., Kiese, M.: Biotransformation of 4-dimethylaminophenol: Reaction with glutathione, and some properties of the reactions products. Chem. biol. Interact. 14, 165–178 (1976)Google Scholar
  7. Gaber, H., Kiese, M., Renner, G.: 2-Dimethylamino-4-(N-methylanilino)-phenol (DMPAP). Structure, actions, biotransformation. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, R 81 (1975)Google Scholar
  8. Green, C. R., Ham, K. N., Tange, J. D.: Kidney lesions induced in rats by p-aminophenol. Brit. med. J. 1969 I, 162–164Google Scholar
  9. Havemann, R., Jung, F., Issekutz, B. v.: Die Bestimmung von Methämoglobin im Blute mit dem lichtelektrischen Kolorimeter. Biochem. Z. 301, 116–124 (1939)Google Scholar
  10. Hinsberg, O., Treupel, G.: Über die physiologische Wirkung des p-Aminophenols und einiger Derivate desselben. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 33, 216–250 (1894)Google Scholar
  11. Huisgen, R., Bayerlein, F., Heydkamp, W.: Die Acylierung der N,N-Dimethylarylamin-oxyde; der Mechanismus der Polonovsky-Reaktion. Ber. dtsch. chem. Ges. 92, 3223–3241 (1959)Google Scholar
  12. Huisgen, R., Heydkamp, W., Bayerlein, F.: Zur Reaktion der N,N-Dimethyl-arylamine mit Diacylperoxyden, der Mechanismus der Entmethylierung. Ber. dtsch. chem. Ges. 93, 363–374 (1960a)Google Scholar
  13. Huisgen, R., Bayerlein, F.: Die Acylierung N,N-disubstituierter Hydroxylamine und die Umsetzung sekundärer Amine mit Diacylperoxyden. Justus Liebigs Ann. Chem. 630, 138–146 (1960b)Google Scholar
  14. Kiese, M.: Oxidation von Anilin zu Nitrosobenzol im Hunde. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 235, 354–359 (1959)Google Scholar
  15. Kiese, M.: Reactions of N,N-dimethylaniline-N-oxide with hemoglobin. Mol. Pharmacol. 3, 9–14 (1967)Google Scholar
  16. Kiese, M.: Methemoglobinemia, a Comprehensive Treatise. Cleveland, Ohio: CRC Press 1974Google Scholar
  17. Kiese, M., Rauscher, E., Weger, N.: The role of N,N-dimethylaniline-N-oxide in the formation of hemiglobin following the absorption of N,N-dimethylaniline. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 254, 253–260 (1966)Google Scholar
  18. Kiese, M., Renner, G., Schlaeger, R.: Mechanism of the autocatalytic formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide. Naunyn-Schmiedebergs Arch. Pharmak. 268, 247–263 (1971)Google Scholar
  19. Kiese, M., Renner, G.: Mechanism of the autocatalytic formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide. Structure and ferrihemoglobin forming activity of the purple dye. Chem. biol. Interact. 12, 415–424 (1976)Google Scholar
  20. Kiese, M., Szinicz, L., Thiel, N., Weger, N.: Ferrihemoglobin and kidney lesions in rats produced by 4-aminophenol or 4-dimethylaminophenol. Arch. Toxicol. 34, 337–340 (1975)Google Scholar
  21. Kiese, M., Weger, N.: Formation of ferrihemoglobin with aminophenols in the human for the treatment of cyanide poisoning. Europ. J. Pharmacol. 7, 97–105 (1969)Google Scholar
  22. Kurz, H., Renner, G.: Eine optische Methode zur Bestimmung von sekundären Aminen. Z. anal. Chem. 249, 369–372 (1962)Google Scholar
  23. Uehleke, H., Stahn, V.: Zur biologischen Bildung von N,N-dimethylanilin-N-oxyd und N,N-dimethylaminoazobenzol-N4-oxyd aus den Aminen sowie ihre Reaktionen mit Hämoglobin und mit Lebermikrosomen. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 255, 287–300 (1966)Google Scholar
  24. Weger, N.: Therapie der Blausäurevergiftung. Med. Mschr. 23, 436–440 (1969)Google Scholar

Copyright information

© Springer-Verlag 1977

Authors and Affiliations

  • Harald Gaber
    • 1
  • Manfred Kiese
    • 1
  • Gerhard Renner
    • 1
  1. 1.Pharmakologisches Institut der Universität MünchenMünchen 2Germany

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