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Deoxyguanosine Adducts of t-4-Hydroxy-2-nonenal Are Endogenous DNA Lesions in Rodents and Humans: Detection and Potential Sources¹

Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595 [F-L. C., R. G. N., J. O., L. Z.], and Division of Pathology, National Institute of Health Sciences, Tokyo 158, Japan [A. N.]

t-4-Hydroxy-2-nonenal (HNE) is a free radical-mediated oxidation product of polyunsaturated fatty acids. As an electrophile, HNE readily binds to proteins and yields diastereomeric cyclic 1,N²-propano adducts with deoxyguanosine (dG). Here, we report the detection and identification of the HNE-derived cyclic 1,N²-propano-dG adducts as endogenous DNA lesions in tissues of untreated rats and humans using a highly sensitive ³²P-postlabeling method in conjunction with high-performance liquid chromatography. These adducts were first verified by their comigration with the synthetic UV standards of HNE-dG adducts. Subsequently, their identities were unequivocally established by two independent reactions. An 37-fold increase in the levels of HNE-dG adducts was observed in the liver DNA of F344 rats after treatment with CCl₄, suggesting that tissue lipid peroxidation is a likely source of their formation. Our studies in vitro further indicate that -6 polyunsaturated fatty acids are likely a unique class of fatty acids involved in HNE-dG adduct formation.

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