Metabolism and DNA binding of 1-nitropyrene and 1-nitrosopyrene in newborn mice

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Abstract
This study was carried out in order to evaluate possible mechanisms responsible for tumor induction by 1-nitropyrene and to provide insights on the higher tumorigenicity of 1-nitrosopyrene than 1-nitropyrene in newborn mouse liver. The "ground mouse" technique was used to follow the development of the metabolism of 1-nitropyrene and 1-nitrosopyrene in newborn and infant mice in vivo. Equimolar doses of 1-nitropyrene and 1-nitrosopyrene were used as in the bioassay reported previously. The compounds were administered by ip injection (100 nmol, day 1; 200 nmol, day 8; 400 nmol, day 15). The ethyl acetate soluble metabolites of 1-nitropyrene were identified as 1-aminopyrene, trans-4,5-dihydro-4,5-dihydroxy-1-nitropyrene, 1-nitropyren-3-ol, 1-nitropyrene-6-ol, and 1-nitropyren-8-ol on the basis of cochromatography with synthetic standards in two different HPLC systems. Nitroreduction of 1-nitropyrene to 1-aminopyrene was observed only in 1 day old mice. Ethyl acetate soluble metabolites of 1-nitrosopyrene were identified as 1-aminopyrene and 1-nitropyrene. The capacity of 1 day old mice to metabolize 1-nitropyrene and 1-nitrosopyrene exceeded those of 8 and 15 day old mice. The extent of nitroreduction of 1-nitrosopyrene exceeded that of 1-nitropyrene. A major DNA adduct, N-(deoxyguanosin-8-yl)-1-1minopyrene, was identified and quantified in liver and in lung, 24 h after carcinogen treatment. The extents of formation of this adduct (pmol/mg of DNA, mean of two experiments) were as follws: 1-nitropyrene (liver, 4.1; lung, 1.2); 1-nitrosopyrene (liver, 30.4; lung, 6.3). The results of this study demonstrate that nitroreduction of 1-nitropyrene to 1-nitrosopyrene, and presumably to the hydroxyamino derivative, is essential for DNA binding in vivo in newborn mice. This pathway may be responsible for intiation of liver tumors.