Metabolism and activation of pancreas specific nitrosamines by pancreatic ductal cells in culture.
Metabolism of 14C labeled N-nitrosobis(2-oxopropyl)amine (BOP), N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydroxypropyl)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 nitrosamine, the evolution of 14CO2 and the labeling of macromolecules. Reduction of BOP to HPOP seems to contribute significantly to the metabolism of the former nitrosamine by pancreatic duct cells, however, redox reactions at the beta-carbon of HPOP or BHP are not extensive. In terms of DNA damage, all three nitrosamines yield methyl and hydroxypropyl adducts. As expected, HPOP and BHP yield higher levels of O6-hydroxypropylguanine than BOP, while the latter yields higher levels of O6-methylguanine. There is no correlation between the ability of these nitrosamines to alkylate duct cell DNA in vitro and their carcinogenic potency in vivo. Concentrations of DNA adducts induced by pancreas specific nitrosamines (PSNs) in cultured duct cells at concentrations comparable 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 formation of active metabolites and DNA adducts may be attributed to the 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 metabolites targeting its DNA in the animal model.
Kokkinakis
D M
DM
Department of Pharmacology, Northwestern University Medical School, Chicago, IL.
Reddy
M K
MK
Norgle
J R
JR
Baskaran
K
K
D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D008297:Male; D008647:Mesocricetus; D008954:Models, Biological; D009154:Mutation; D009602:Nitrosamines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*
D002250:Carbon Radioisotopes; D002273:Carcinogens; D009602:Nitrosamines; C012457:diisopropanolnitrosamine; C013622:nitrosobis(2-oxopropyl)amine; C013624:N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine; D004247:DNA