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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 2, 2003; DOI: 10.1124/jpet.103.052639

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Received for publication April 3, 2003.
Revised April 24, 2003.
Accepted for publication April 28, 2003.

Oxidative stress-induced homologous recombination as a novel mechanism for phenytoin-initiated toxicity

Louise M. Winn 1*, Perry M. Kim 1, Jac A. Nickoloff 2

1 Queen's University 2 University of New Mexico

* Address correspondence to: E-mail: winnl{at}biology.queensu.ca

Abstract

While the mechanism(s) of phenytoin-initiated toxicity is unknown, phenytoin can be enzymatically bioactivated to a reactive intermediate leading to increased formation of reactive oxygen species (ROS) which can damage essential macromolecules including DNA. The oxidation of DNA can induce DNA double-strand breaks (DSBs), which may be repaired through homologous recombination. Increased levels of DSBs may induce hyper-recombination leading to deleterious genetic changes. We hypothesize that these genetic changes mediate phenytoin-initiated toxicity. To investigate this hypothesis we used a Chinese hamster ovary (CHO) cell line containing a neo direct repeat recombination substrate to determine whether phenytoin- initiated DNA oxidation increases homologous recombination. Cells were treated with 0-800 µM phenytoin for 5 or 24 hr, and homologous recombination frequencies and recombinant product structures were determined. Phenytoin-initiated DNA oxidation was determined by measuring the formation of 8-hydroxy-2'- deoxyguanosine (8-OH-2dG). We demonstrate that phenytoin increases both DNA oxidation and homologous recombination in a concentration- and time-dependent manner. All recombination products analyzed arose via gene conversion without associated crossover. Our data demonstrate that phenytoin-initiated DNA damage can induce homologous recombination, which may be a novel mechanism mediating chemical-initiated toxicity.


Key words: CHO 3-6 cells, DNA oxidation, homologous recombination, oxidative stress, phenytoin, toxicity


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