There is compelling evidence for a role for two types of chemical, tobacco specific nitrosamines and heterocyclic amines, in the induction of pancreatic ductal adenocarcinoma in humans. There are animal models for this form of cancer involving tobacco specific nitrosamines and other experimental evidence implicating heterocyclic amines. We propose to examine the actions of a representative amine (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine (PhlP) and nitrosamine (4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)) and the carcinogenic nitrosamine MIP (N-nitrosomethyl (2-oxopropyl)amine) in pancreatic duct epithelial cells (DEC) from humans and from the appropriate rodent species and strains. We will concentrate on the metabolic activation of these chemicals focussing on the enzyme(s) that are involved in their metabolism.
Our aim here is to determine those enzymes that may predispose humans to the pancreatrophic actions of environmental chemicals and to attempt to define groups who are at risk for pancreas cancer induction. We will determine the profile of metabolizing enzymes in both human and rodent DEC, focussing on those enzymes that are known to be involved in the activation of carcinogens. Having established this profile we will examine the ability of specific enzymes, mostly P450 isoforms, to metabolize MIO, NNAL and PhlP using the profile of metabolites and the ability to induce mutations. The ability of these carcinogens, activated by enzymes that are identified in the earlier aims, to neoplastically transform DEC will be measured. Lastly we will examine the capacity of DEC to repair different forms of DNA damage. A crucial factor in determining susceptibility might be the ability of DEC to repair DNA damage caused by the putative carcinogens. Our understanding of chemically induced pathological conditions is seriously hindered by a lack of knowledge of the ability of these cells to metabolize chemicals and to repair the genetic consequences of this activation. This proposal seeks to address some of these concerns and issues.
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