Promutagenic etheno−DNA adducts in multistage mouse skin carcinogenesis

• Verfasst von: Nair, Jagadeesan [VerfasserIn]
• Verfasst von: Fürstenberger, Gerhard [VerfasserIn]
• Verfasst von: Bürger, Friederike [VerfasserIn]
• Verfasst von: Marks, Friedrich [VerfasserIn]
• Verfasst von: Bartsch, Helmut [VerfasserIn]
• Titel: Promutagenic etheno−DNA adducts in multistage mouse skin carcinogenesis
• Titelzusatz: Correlation with Lipoxygenase-Catalyzed Arachidonic Acid Metabolism
• Verf.angabe: Jagadeesan Nair, Gerhard Fürstenberger, Friederike Bürger, Friedrich Marks, and Helmut Bartsch
• E-Jahr: 2000
• Jahr: July 8, 2000
• Umfang: 7 S.
• Fussnoten: Gesehen am 28.01.2021
• Titel Quelle: Enthalten in: Chemical research in toxicology
• Ort Quelle: New York, NY : ACS Publ., 1988
• Jahr Quelle: 2000
• Band/Heft Quelle: 13(2000), 8, Seite 703-709
• ISSN Quelle: 1520-5010
• DOI: doi:10.1021/tx000045d
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1745926577

Abstract

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.