Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 285, Issue 4, pp 315–324 | Cite as

The mechanism of halothane binding to microsomal cytochrome P450

  • D. Mansuy
  • W. Nastainczyk
  • V. Ullrich
Article

Summary

The unusual difference spectrum obtained with halothane and reduced rat liver microsomal cytochrome P450 can be simulated by addition of trifluoro diazoethane to dithionite reduced microsomes. Chemical evidence and model reactions suggest that in both cases a trifluoromethyl carbene complex is formed with the reduced hemoprotein. The spectral dissociation constants of the two species are similar as are their competitive reactions with carbon monoxide. The partial destruction of the carbenoid-cytochrome P450 complex characterizes the ligand as a highly reactive species. It is assumed that under anaerobic conditions this complex is formed by a two electron reduction of halothane and that covalent binding to microsomal proteins proceeds by this carbenoid species. A possible relationship to the hepatotoxicity of polyhalogenated compounds and anesthetics is discussed.

Key words

Halothane Microsomal Cytochrome P450 Carbenoid Reductive Dehalogenation 

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Copyright information

© Springer-Verlag 1974

Authors and Affiliations

  • D. Mansuy
    • 1
  • W. Nastainczyk
    • 1
  • V. Ullrich
    • 1
  1. 1.Fachbereich Theoretische MedizinUniversität des SaarlandesHomburg (Saar)Federal Republic of Germany

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