Mutagenic activation of N-nitrosobis(2-oxopropyl)amine by pancreatic juice and assessment of its ductal tumorigenicity following intraductal administration in dogs

Abstract

Conclusion: The results suggest that systemic administration (s.c. and i.p.) of BOP induces liver damage due to BOP itself and/or its metabolites which might be formed in the liver and that interaction of BOP itself in the pancreatic duct with pancreatic juice plays an important role for pancreatic duct tumorigenicity.

Methods: Mutagenic activation and pancreatic duct tumorigenicity of N-nitrosobis (2-oxopropyl)amine (BOP) administered s.c., i.p., and i.d. were studied in dogs.

Results: Following i.p. administration of BOP, N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP), but not BOP, were detected in pancreatic juice, while following i.d. administration, only BOP was detected. The pancreatic juice of one dog that received 100 mg of BOP i.d. showed positive mutagenicity towards Salmonella typhimurium TA100, but the pancreatic juice of two dogs that received 100 mg of BOP i.p. was not mutagenic. BOP showed clear mutagenicity in the presence of pancreatic juice from untreated dogs, but the pancreatic juice could not activate HPOP and BHP to mutagens. BOP administered sc for 2 wk (total dose: 600 mg) induced clinical toxicity, nausea, vomiting, and loss of appetite at 10 wk. BOP administered i.p. for 4 mo (total dose: 2000 mg) induced liver damage at 6 mo, but no pancreatic injury. BOP administered i.d. for 6.5 or 12 mo (total dose: 2500 or 4700 mg, respectively) induced papillary hyperplasia and dysplasia of duct epithelial cells and ductal proliferation with fibrosis.