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Hydrogen Peroxide Supports Hepatocyte P450 Catalysed Xenobiotic/Drug Metabolic Activation to form Cytotoxic Reactive Intermediates

  • T. S. Chan
  • M. Moridani
  • A. Siraki
  • H. Scobie
  • K. Beard
  • M. A. Eghbal
  • G. Galati
  • P. J. O’Brien
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 500)

Abstract

  1. 1.

    A H2O2 generating system markedly increased the cytotoxicity of catechols, hydroquinone, in isolated hepatocytes, but not in P450 inhibited hepatocytes.

     
  2. 2.

    H2O2or NADPH supported microsomal catalysed GSH conjugate formation with catechols or hydroquinone. Cytochrome P450 inhibitors inhibited conjugate formation. However, superoxide dismutase inhibited NADPH, but did not affect H2O2supported GSH conjugate formation. The conjugate formed with dihydrocaffeic acid was identified as a mono-GSH conjugate indicating that the o-quinone was the major metabolite formed.

     
  3. 3.

    Dopamine (a catecholamine) induced cytotoxicity was prevented by inhibitors of monoamine oxidase (MAO) or P450, but was markedly increased by hepatocyte catalase inhibition or NAD(P)H:quinone oxidoreductase inhibition. This suggests that H2O2formed by the mitochondrial metabolism of monoamine oxidase then oxidised dopamine to cytotoxic o-quinone catalysed by P450. Dihydrocaffeic acid cytotoxicity was also increased by the monoamine oxidase substrate tyramine.

     
  4. 4.

    It is concluded that polyphenolics are oxidised by H2O2/P450 in hepatocytes to form quinone metabolites.

     

Keywords

Caffeic Acid Monoamine Oxidase Conjugate Formation Resistant Respiration Hydroperoxide Linoleic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • T. S. Chan
    • 1
  • M. Moridani
    • 1
  • A. Siraki
    • 1
  • H. Scobie
    • 1
  • K. Beard
    • 1
  • M. A. Eghbal
    • 1
  • G. Galati
    • 1
  • P. J. O’Brien
    • 2
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada
  2. 2.Corresponding authorCanada

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