Promutagenic etheno−DNA adducts in multistage mouse skin carcinogenesis: Correlation with Lipoxygenase-Catalyzed Arachidonic Acid Metabolism
Formation of the lipoxygenase-catalyzed metabolites of arachidonic acid, 8-hydroxyeicosatetraenoic acid (8-HETE) and 12-hydroxyeicosatetraenoic acid (12-HETE), and of the exocyclic DNA adducts 1,N6-ethenodeoxyadenosine (εdA) and 3,N4-ethenodeoxycytidine (εdC) was investigated in NMRI mouse skin carc...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
July 8, 2000
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| In: |
Chemical research in toxicology
Year: 2000, Jahrgang: 13, Heft: 8, Pages: 703-709 |
| ISSN: | 1520-5010 |
| DOI: | 10.1021/tx000045d |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/tx000045d Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/tx000045d 
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| Verfasserangaben: | Jagadeesan Nair, Gerhard Fürstenberger, Friederike Bürger, Friedrich Marks, and Helmut Bartsch |
| Zusammenfassung: | Formation of the lipoxygenase-catalyzed metabolites of arachidonic acid, 8-hydroxyeicosatetraenoic acid (8-HETE) and 12-hydroxyeicosatetraenoic acid (12-HETE), and of the exocyclic DNA adducts 1,N6-ethenodeoxyadenosine (εdA) and 3,N4-ethenodeoxycytidine (εdC) was investigated in NMRI mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). In reversible papillomas obtained after 20 weeks of TPA treatment, 15- and 68-fold higher contents of 8-HETE and 12-HETE, respectively, were observed, which were paralleled by 12- and 9-fold increased amounts of εdA and εdC, respectively. When compared to the level in vehicle-treated control skin, these elevations were statistically significant. In irreversible papillomas harvested 20 weeks after the last TPA treatment, the levels of HETEs and etheno−DNA adducts were found to be slightly reduced, as compared to those in reversible papillomas, but were still increased over control levels in age-matched mice. Comparison of mean group values by simple regression analysis showed a close positive correlation between HETE and etheno−DNA adduct levels. Consistent with the miscoding properties of εdA causing mainly A → T transversions, its increased formation in papillomas could thus contribute to this type of mutation in codon 61 of cHa-ras, shown to be a hallmark of DMBA-initiated and TPA-promoted mouse skin carcinogenesis. Although direct evidence that etheno adducts are derived from lipoxygenase-catalyzed metabolites of arachidonic acid is missing, our results implicate DNA damage by oxidative stress and lipid peroxidation as a cause of genetic instability observed at late stages of tumor promotion in mouse skin carcinogenesis. |
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| Beschreibung: | Gesehen am 28.01.2021 |
| Beschreibung: | Online Resource |
| ISSN: | 1520-5010 |
| DOI: | 10.1021/tx000045d |