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DNA alkylation in the hamster induced by two pancreatic carcinogens
D M Kokkinakis1, D G Scarpelli
1Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611.
Abstract:
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.
Insights
N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) are carcinogens that alkylate DNA in Syrian hamsters. BOP shows higher DNA alkylation and organ targeting than HPOP, correlating with its greater carcinogenic potency.
Area of Science:
- Toxicology and Carcinogenesis
- Molecular Biology
- Biochemistry
Background:
- N-Nitrosobis(2-oxopropyl)amine) (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) are known carcinogens.
- These compounds alkylate DNA and macromolecules in various organs.
Purpose of the Study:
- To investigate the DNA adducts formed by BOP and HPOP in Syrian hamsters.
- To compare the DNA alkylation patterns and organ distribution of BOP and HPOP.
- To correlate DNA adduct formation with the known carcinogenic potency of these nitrosamines.
Main Methods:
- Administration of single-labeled [1-14C]BOP or HPOP to Syrian hamsters.
- Quantitation of DNA adducts, specifically N7-methylguanine and O6-methylguanine, using UV spectroscopy and radioactivity.
- Identification of N7-(2-hydroxypropyl)guanine adducts.
- Comparison of alkylation levels between BOP and HPOP treated hamsters at equivalent doses.
Main Results:
- N7-methylguanine and O6-methylguanine were major DNA adducts, with N7-methylguanine accounting for ~60% of liver DNA alkylation.
- N7-(2-hydroxypropyl)guanine was identified as another significant adduct.
- The specific activity of N7-methylguanine indicated that gamma carbons of nitrosamines are not involved in methylation.
- BOP induced higher levels of DNA alkylation in kidney, lungs, and pancreas compared to HPOP.
- Ratios of N7-methylguanine in BOP vs. HPOP treated hamsters ranged from 3.1 (kidney) to 7.0 (pancreas).
Conclusions:
- The DNA alkylation patterns by BOP and HPOP support their differing carcinogenic potencies and organotropic effects.
- BOP is a more potent alkylating agent than HPOP, particularly in the kidney, pancreas, and lungs.
- The study elucidates the molecular mechanisms underlying the differential carcinogenicity of these nitrosamines.