DNA oxidation induced by cyclooxygenase-2.
The inducible form of cyclooxygenase, COX-2, has been shown to be overexpressed in various types of tumors, including colon and prostate cancer. Several studies indicate that COX-2 inhibition can be beneficial for the prevention of these types of cancer. Since COX-2 reactions involve production of reactive oxygen radicals that can potentially damage biological macromolecules, we explored the possibility that DNA and/or nucleosides can be oxidized during cyclooxygenase reactions. When DNA or nucleosides were incubated with COX-2 and arachidonic acid, a significant increase in the amount of 8-oxo-2'-deoxyguanosine was observed. This increase was enzyme-dependent and could be prevented by COX-2 inhibitors as well as by antioxidants. These data indicate that peroxyl radicals or other oxidized species formed during conversion of arachidonic acid to prostaglandin G(2) might be responsible for the observed oxidation. These results suggest also that overexpression of COX-2 in inflammatory diseases places an additional burden on antioxidative defenses of the cell, which might contribute to DNA oxidation and the induction of mutations.
Nikolic
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Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-7231, USA.
van Breemen
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RB
D051546:Cyclooxygenase 2; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D007527:Isoenzymes; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases