METABOLISM AND ACTIVATION OF PANCREAS SPECIFIC NITROSAMINES BY PANCREATIC DUCTAL CELLS IN CULTURE

Metabolism of C-14 labeled N-nitrosobis(2-oxopropyl)amine (BOP), N-nit roso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydr oxypropyl)amine (BHP) by pancreatic duct cells in culture involves the following two pathways: reduction or oxidation reactions at the beta- carbon which result in the inter-conversion of these nitrosamines and activation reactions which result in the decomposition of the nitrosam ine, the evolution of (CO2)-C-14 and the labeling of macromolecules. R eduction of BOP to HPOP seems to contribute significantly to the metab olism of the former nitrosamine by pancreatic duct cells, however, red ox reactions at the beta-carbon of HPOP or BHP are not extensive. In t erms of DNA damage, all three nitrosamines yield methyl and hydroxypro pyl adducts. As expected, HPOP and BHP yield higher levels of O6-hydro xypropylguanine than BOP, while the latter yields higher levels of O6- methylguanine. There is no correlation between the ability of these ni trosamines to alkylate duct cell DNA in vitro and their carcinogenic p otency in vivo. Concentrations of DNA adducts induced by pancreas spec ific nitrosamines (PSNs) in cultured duct cells at concentrations comp arable to those found in the pancreatic juice of animals treated with BOP, are almost an order of magnitude lower than those induced in the pancreas of such animals. Discrepancies between in vitro and in vivo f ormation of active metabolites and DNA adducts may be attributed to th e decline of the cells' ability to activate PSNs during culturing. In the same vein, the ductal cell may not be the main source of active me tabolites targeting its DNA in the animal model.