DNA alkylation in the hamster induced by two pancreatic carcinogens.
N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) alkylate DNA and other macromolecules in the liver, kidney, pancreas, and lungs when injected s.c. in the Syrian hamster. Two of the most abundant DNA adducts found were the N7-methylguanine and O6-methylguanine, which in the liver accounted for about 60% of total DNA alkylation. A third adduct which was invariably found in liver and kidneys, but could not always be detected in pancreas and lungs, was identified as N7-(2-hydroxypropyl)guanine. Quantitation of N7-methylguanine by its UV spectrum and radioactivity, following administration of single-labeled [1-14C]BOP or HPOP, showed that the specific activity of this adduct was one half that of the nitrosamine. This excludes participation of the gamma carbons of these nitrosamines in methylation reactions and indicates that intermediates in which scrambling of the alpha and gamma carbons is possible are not involved in yielding the ultimate methylating agent. Finally, a comparison of the alkylation levels caused by equivalent doses of BOP and HPOP showed that BOP targeted DNA and other cytoplasmic components of kidney, lungs, and pancreas more extensively than HPOP. Ratios of N7-methylguanine in BOP versus HPOP treated hamsters, at doses less than 40 mg/kg body weight, were 3.1 in the kidney, 7.0 in the pancreas, 3.9 in the lung, and only 3.5 in the liver. These ratios are in accordance with the greater carcinogenic potency of BOP compared to HPOP and also the different organotropic properties of the two carcinogens.
Kokkinakis
D M
DM
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611.
Scarpelli
D G
DG
D000478:Alkylation; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000139:chemically induced; D014018:Tissue Distribution
D002273:Carcinogens; D009602:Nitrosamines; C013622:nitrosobis(2-oxopropyl)amine; C013624:N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine; D004247:DNA