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,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.
Nair
J
J
Division of Toxicology and Cancer Risk Factors and Division of Biochemistry of Tissue-Specific Regulation, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Fürstenberger
G
G
Bürger
F
F
Marks
F
F
Bartsch
H
H
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000032:analysis / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000032:analysis; D003839:Deoxyadenosines / Q000032:analysis / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006893:Hydroxyeicosatetraenoic Acids / Q000032:analysis / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D018736:DNA Adducts; D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D006893:Hydroxyeicosatetraenoic Acids; D003841:Deoxycytidine; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C032221:1,N(6)-ethenodeoxyadenosine; C032222:3,N(4)-ethenodeoxycytidine; C047628:8-hydroxyeicosatetraenoic acid; D008084:Lipoxygenase