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Karam El-Bayoumy,¹ Bruce Johnson,² Ajit K. Roy,¹ Pramod Upadhyaya,¹ Syrus Partian,¹ and Stephen S. Hecht¹

¹Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York; ²University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, Tucson, Arizona

Abstract

On the basis of ³²P-postlabeling analysis, treatment of rats with 1-nitropyrene (1-NP) resulted in the formation of multiple DNA adducts in the liver, mammary glands, and peripheral lymphocytes. The one adduct resulting from nitroreduction, N-(deoxyguanosin-8-yl) -1-aminopyrene, constitutes only a minor component among the adducts. In the present study, incubation of calf thymus DNA with mutagenic ring-oxidized metabolites of 1-NP in vitro in the presence and absence of xanthine oxidase also resulted in the formation of multiple adducts. On the basis of their chromatographic behavior, it appears that DNA adducts derived from such metabolites may have been formed in vivo ; however, this needs to be confirmed. [³H]1-NP was given to male and female F344 rats and Sprague-Dawley rats by gavage at five dose levels in the range of 0.1 to 1000 µg/kg bw. This led to stable hemoglobin adducts accounting for 0.08 ± 0.05% of the dose (n = 3 rats) . The radioactivity associated with hemoglobin following administration of [³H]1-NP was cleared with a half-life of about 14 days, which is faster than that of unmodified erythrocytes in the rat (t_1/2=30 days) . Treatment of the hemoglobin with 1% HCl in acetone, to precipitate the globin, released the radioactivity ; it was all bound to the heme moiety. The structures of the heme adducts have not been elucidated ; yet, because of their stability, they may be useful as dosimeters for human exposure to 1-NP. The results of this study demonstrate the potential of using hemoglobin adducts of 1-NP as dosimeters of uptake and metabolic activation of nitropolynuclear aromatic hydrocarbons (NO₂-PAH) . These indicators are a prerequisite for cancer risk assessment of NO₂-PAH. -- Environ Health Perspect 102(Suppl 6) :31-37 (1994)

Key words: nitropyrene, ³²P-postlabeling, DNA adducts, N-(deoxyguanosin-8-yl) -1-aminopyrene (N-dG-AP) , K-region oxide-DNA adducts, protein adducts, heme adducts