Metabolism of Pancreatic Carcinogens N-Nitroso-2, 6-Dimethylmorphline and N-Nitrosobis(2-oxopropyl)amine by Microsomes and Cytosol of Hamster Pancreas and Liver

Liver preparations from Syrian golden hamsters catalyze the metabolism of the pancreatic carcinogen N-nitroso-2, 6-dimethylmorpholine largely to N-nitroso(2-hydroxypropy1)(2-oxopropyl)amine (HPOP). This reaction is catalyzed by a mixed-function oxidase in the presence of reduced nicotinamide adenine dinucleotide phosphate and oxygen at a rate of 3.8 nmol/min/mg of protein, and it is inhibited by known cytochrome P-450-specific inhibitors. A second potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) is converted to HPOP by hamster liver in which two enzyme systems appear to be involved. The first is a reductase associated with microsomes which reduces BOP to HPOP in the presence of reduced nicotinamide adenine dinucleotide at a rate of 9.1 nmol/min/mg of protein. The second enzyme is a cytosolic one which catalyzes the same reaction at a slower rate (2.3 nmol/min/mg of protein) and is more effective with reduced nicotinamide adenine dinucleotide phosphate as cofactor. Based on the amount of protein in hepatic cytosol and endoplasmic reticulum, the two enzymes may be involved to a similar extent in the reduction of BOP to HPOP in the liver. Pancreas, on the other hand, lacks the microsomal reductase for BOP but contains a cytosolic enzyme which catalyzes its reduction in the presence of reduced nicotinamide adenine dinucleotide phosphate at a rate of 0.35 nmol/min/mg of protein. Since both pancreatic carcinogens N-nitroso-2, 6-dimethylmorpholine and BOP are metabolized to HPOP in the liver at rates much higher than those observed in the target organ pancreas, it is suggested that the liver may play an important role in pancreatic carcinogenesis in the hamster by these compounds.