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DNA Alkylation in the Hamster Induced by Two Pancreatic Carcinogens¹

Department of Pathology and the Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611

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 pancreases 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 carbons of these nitrosamines in methylation reactions and indicates that intermediates in which scrambling of the and 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 8.1 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.

¹ This work was supported by NCI Grant CA-42983.

² To whom requests for reprints should be addressed, at Department of Pathology and the Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611.

Received 9/ 7/88. Revised 2/14/89. Accepted 3/20/89.