Promutagenic etheno-DNA adducts in multistage mouse skin carcinogenesis: correlation with lipoxygenase-catalyzed arachidonic acid metabolism.

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,N(6)-ethenodeoxyadenosine (epsilondA) and 3, N(4)-ethenodeoxycytidine (epsilondC) 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 epsilondA and epsilondC, 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 epsilondA 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.

• Authors: J Nair, G Fürstenberger, F Bürger, F Marks, H Bartsch
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 13 Issue 8 Pg. 703-9 (Aug 2000) ISSN: 0893-228X [Print] United States
• PMID: 10956057 (Publication Type: Journal Article)

Chemical References

• DNA Adducts
• DNA, Neoplasm
• Deoxyadenosines
• Hydroxyeicosatetraenoic Acids
• Deoxycytidine
• Arachidonic Acid
• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
• 1,N(6)-ethenodeoxyadenosine
• 3,N(4)-ethenodeoxycytidine
• 8-hydroxyeicosatetraenoic acid
• Lipoxygenase

Topics

• 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid (analysis, metabolism)
• Animals
• Arachidonic Acid (metabolism)
• Chromatography, High Pressure Liquid
• DNA Adducts (analysis, biosynthesis)
• DNA, Neoplasm (analysis)
• Deoxyadenosines (analysis, metabolism)
• Deoxycytidine (analogs & derivatives, analysis, metabolism)
• Female
• Gas Chromatography-Mass Spectrometry
• Hydroxyeicosatetraenoic Acids (analysis, metabolism)
• Lipoxygenase (metabolism)
• Mice
• Mutagenesis
• Papilloma (chemically induced, genetics, metabolism)
• Skin Neoplasms (chemically induced, genetics, metabolism)
• Up-Regulation