Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins.
Epidemiological data suggest that dietary antioxidants play a protective role against cancer. This has led to the proposal that dietary supplementation with antioxidants such as vitamin C (vit C) may be useful in disease prevention. However, vit C has proved to be ineffective in cancer chemoprevention studies. In addition, concerns have been raised over potentially deleterious transition metal ion-mediated pro-oxidant effects. We have now determined that vit C induces lipid hydroperoxide decomposition to the DNA-reactive bifunctional electrophiles 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal. The compound 4,5-Epoxy-2(E)-decenal is a precursor of etheno-2'-deoxyadenosine, a highly mutagenic lesion found in human DNA. Vitamin C-mediated formation of genotoxins from lipid hydroperoxides in the absence of transition metal ions could help explain its lack of efficacy as a cancer chemoprevention agent.
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Center for Cancer Pharmacology, University of Pennsylvania, 1254 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
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D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry; D001205:Ascorbic Acid / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002021:Buffers; D003300:Copper / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008041:Linoleic Acids / Q000737:chemistry* / Q000378:metabolism; D008054:Lipid Peroxides / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins; D008670:Metals / Q000494:pharmacology; D009153:Mutagens / Q000737:chemistry* / Q000378:metabolism; D016877:Oxidants / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
C096140:4,5-epoxy-2-decenal; C403894:4-oxo-2-nonenal; D000447:Aldehydes; D000975:Antioxidants; D002021:Buffers; D018736:DNA Adducts; D004852:Epoxy Compounds; D005296:Ferrous Compounds; D007527:Isoenzymes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D008565:Membrane Proteins; D008670:Metals; D009153:Mutagens; D016877:Oxidants; C038649:13-hydroperoxy-9,11-octadecadienoic acid; D003300:Copper; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C027576:4-hydroxy-2-nonenal; D001205:Ascorbic Acid