Journal
TOXICOLOGY IN VITRO
Volume 21, Issue 4, Pages 566-575Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2006.11.002
Keywords
cytochrome P450; hydroquinone; benzoquinone; P450; destruction; hydroxyl radicals; ESR
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Reactive metabolites of benzene 1,4-benzoquinone and 1,4-hydroquinone exert their toxic effects through covalent and/or oxidative damage to DNA and proteins. Since minipigs have been proposed as a suitable model species in toxicological and pharmacological research, the aim of this study was to explore mechanisms by which catechol, 1,4-hydroquinone and 1,4-benzoquinone destroy cytochrome P450 (P450) and induce oxidative stress in minipig liver microsomes. Our second goal was to assess the usefulness of minipig liver microsomes as a model system for the testing of the production of oxidative stress by clinically relevant quinone-containing compounds, e.g. anthracyclines. Of the three benzene metabolites tested, the highest P450 destruction was caused by 1,4-benzoquinone. This destructive effect did not correlate with the production of hydroxyl radicals as measured by ESR spin trapping which was the highest in samples containing 1,4-hydroquinone. Our results confirm previous findings that 1,4-benzoquinone exerts its effect mainly by direct attack on macromolecules while 1,4-hydroquinone rather stimulates the production of reactive oxygen species. Doxorubicin stimulated the production of hydroxyl radicals and the destruction of P450 similarly as 1,4-hydroquinone. Minipig liver microsomes should be further tested as a possibly suitable model system for the testing of potential modulators of the toxicity of doxorubicin. (C) 2006 Elsevier Ltd. All rights reserved.
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