Metabolism and DNA binding of 1-nitropyrene and 1-nitrosopyrene in newborn mice
- American Health Foundation, Valhalla, NY (USA)
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-nitropyren-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-aminopyrene, 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 follows: 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 initiation of liver tumors.
- OSTI ID:
- 5015164
- Journal Information:
- Chemical Research in Toxicology; (USA), Journal Name: Chemical Research in Toxicology; (USA) Vol. 1:4; ISSN CRTOE; ISSN 0893-228X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ANIMALS
AROMATICS
BIOCHEMICAL REACTION KINETICS
BODY
CARCINOGENESIS
DIGESTIVE SYSTEM
DNA ADDUCTS
GLANDS
HYDROCARBONS
KINETICS
LIVER
LUNGS
MAMMALS
METABOLISM
MICE
NEONATES
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
POLYCYCLIC AROMATIC HYDROCARBONS
REACTION KINETICS
RESPIRATORY SYSTEM
RODENTS
VERTEBRATES