Enzymatic reduction of beta-ketonitrosamines

Area of Science:

• Biochemistry
• Toxicology
• Carcinogenesis

Background:

• N-nitrosobis(2-oxopropyl)amine) (BOP) and N-nitroso(2-oxopropyl)propylamine (NOPPA) are nitrosamines with carcinogenic potential.
• Species-specific differences in cancer induction by BOP suggest variations in metabolic pathways.

Purpose of the Study:

• To investigate the reduction of BOP and NOPPA by hepatic and pancreatic enzymes in Syrian golden hamsters and Sprague-Dawley rats.
• To determine the role of pancreatic reduction in BOP-induced pancreatic cancer.

Main Methods:

• Incubation of hepatic and pancreatic cytosol and microsomes with BOP and NOPPA.
• Assay of reductase activity using NADH and NADPH as cofactors.
• Comparison of enzyme activity between species and tissues.

Main Results:

• Both hepatic and pancreatic fractions reduced BOP and NOPPA, with activity dependent on the fraction and cofactor.
• Hamster hepatic fractions showed higher activity than rat fractions; BOP was a better substrate than NOPPA.
• Pancreatic cytosol exhibited reductase activity, with hamster cytosol utilizing both NADH and NADPH, while rat cytosol required NADPH.
• BOP was the preferred substrate for pancreatic enzymes, with similar activity in rats and hamsters when NADPH was present.

Conclusions:

• Hepatic and pancreatic enzymes contribute to the metabolism of BOP and NOPPA in both rats and hamsters.
• The observed species-specific differences in enzyme activity may influence carcinogenicity.
• Pancreatic reduction of BOP is unlikely to be a major factor in the species-specific induction of pancreatic cancer by BOP.