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In Vivo and Microsomal Metabolism of the Pancreatic Carcinogen N-Nitrosobis(2-oxopropyl)amine by the Syrian Golden Hamster¹

The School of Public Health, University of Illinois at the Medical Center, Chicago, Illinois 60680

N-Nitrosobis(2-oxopropyl)amine (BOP), a ß-oxidized metabolite of di-n-propylnitrosamine, is a potent carcinogen of the pancreas in Syrian golden hamsters. In the present studies, we investigated the in vivo metabolism of BOP in hamsters as well as its in vitro metabolism by the hamster pancreatic, liver, kidney, and lung microsomes. Data are also presented utilizing high-pressure liquid chromatography separation methodology for the BOP metabolites, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP).

Groups of three hamsters given BOP (50 mg/kg i.p.) were sacrificed at intervals between 15 and 240 min, and the pancreas, liver, lung, kidney, and other tissues were removed; blood and urine were also collected. At 15 min, HPOP levels were highest in the pancreas (34 µg/g) followed by liver, lung, and kidney (14 to 16 µg/g) and testes and brain (5 to 8 µg/g). However, BHP levels were significantly lower (liver and kidney, 5 to 7 µg/g) or undetectable (pancreas). Plasma levels of HPOP and BHP were 25 and 4 µg/ml, respectively. Both HPOP and BHP (when measurable) decreased with time. The half-life of HPOP in the pancreas (75 min) was longer than that in other tissues (45 to 57 min). However, the half-life of BHP in plasma and tissues was 72 to 90 min, which was similar to the HPOP half-life in the pancreas. HPOP and BHP levels in the urine increased with time, reaching a maximum of 217 µg HPOP per ml at 1 hr and 168 µg BHP per ml at 4 hr. Microsomal preparations from selected tissues were capable also of converting BOP to HPOP; the rate of HPOP formation by the pancreatic microsomes was approximately 4.7 ng/mg protein per min, which was significantly lower than the rates in the liver, kidney, and lung microsomes.

The presence of HPOP, a presumed proximate carcinogenic metabolite of BOP, in the pancreas appears to be of significance in the understanding of specificity of BOP for the hamster pancreas.

¹ This work was supported by National Cancer Institute (NIH) Grant CA-20914.

Received 7/10/80. Accepted 11/ 4/80.