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

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Biological Reactive Intermediates VI

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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Author information

Authors and Affiliations

  1. Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 2S2, Canada

    T. S. Chan, M. Moridani, A. Siraki, H. Scobie, K. Beard, M. A. Eghbal & G. Galati

  2. Corresponding author, Canada

    P. J. O’Brien

Authors
  1. T. S. Chan
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  2. M. Moridani
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  3. A. Siraki
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  4. H. Scobie
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  5. K. Beard
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  6. M. A. Eghbal
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  7. G. Galati
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  8. P. J. O’Brien
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Editor information

Editors and Affiliations

  1. Université René Descartes, Paris, France

    Patrick M. Dansette

  2. Rutgers University and The Environmental & Occupational Health Sciences Institute, Piscataway, New Jersey, USA

    Robert Snyder

  3. CNRS, Paris, France

    Marcel Delaforge

  4. University of Surrey, Guildford, Surrey, England

    G. Gordon Gibson

  5. Institute of Toxicology and Environmental Health, The Technical University of Munich, Munich, Germany

    Helmut Greim

  6. Medical University of South Carolina, Charleston, South Carolina, USA

    David J. Jollow

  7. University of Texas, Austin, Texas, USA

    Terrence J. Monks

  8. University of Arizona, Tucson, Arizona, USA

    I. Glenn Sipes

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© 2001 Springer Science+Business Media New York

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Chan, T.S. et al. (2001). Hydrogen Peroxide Supports Hepatocyte P450 Catalysed Xenobiotic/Drug Metabolic Activation to form Cytotoxic Reactive Intermediates. In: Dansette, P.M., et al. Biological Reactive Intermediates VI. Advances in Experimental Medicine and Biology, vol 500. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0667-6_34

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  • DOI: https://doi.org/10.1007/978-1-4615-0667-6_34

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5185-6

  • Online ISBN: 978-1-4615-0667-6

  • eBook Packages: Springer Book Archive

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