MECHANISM OF NITROSAMINE ALKYLATION OF DNA AND RNA

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The objective is to understand the carcinogenic action of nitrosamines and the mechanism of their tissue specific effects. Specifically, this proposal addresses the mechanism of tumor initiation by BOP and related Beta-oxidized nitrosamines which induce tumors of the pancreatic ducts and ductules in Syrian hamsters. These tumors are particularly interesting and important because of their similarity to pancreatic tumors in man which are also principally ductal in nature. The mechanism of DNA methylation by BOP will be investigated using an in vitro assay system. Presence of the activating enzyme(s) in pancreatic tissue will be determined. Using a new, highly sensitive method for analysis of 06-methylguanine, formation and repair of this modified base in isolated acinar cells and islets of hamster and rat will be measured. The results of this study will provide information regarding the nature of the target cell for BOP, and whether susceptible and non-susceptible (rat) species differ with respect to DNA methylation. In order to assess directly whether the liver plays a role in the activation of BOP to a methylating agent for the pancreas, methylation of pancreatic DNA by BOP will be determined in hamsters that have received a partial hepatectomy and also in the isolated perfused pancrease. To assess the contribution of hepatic metabolism, perfusate for the pancreas will be first perfused through an intact hamster liver. Long-term effects of BOP and HPOP on cultured hamster islets will be evaluated by measuring Beta-cell function (insulin secretion). Stimulation of mitosis in cultured islets by high glucose concentrations will be used to optimize the chances of obtaining in vitro transformation. Furthermore, stimulation of mitosis in vivo by intravenous glucose infusion in hamsters will be used to determine whether islet precursor cells play a role in the tumorigenesis of BOP. Integration of the results from these interrelated aims will provide information concerning the nature of the target cell and the mechanism of tumor initiation by BOP and related nitrosamines in the hamster pancreas, and reasons why the rat pancreas is resistant to these compunds.