A screening system has been used to discover potential dietary-related inhibitors against the tumorigenic effects of nitrosamines. There are three sets of experiments in this screening system: 1. in vitro metabolism; 2. in vivo metabolism and/or DNA adduct formation; 3. induction of DNA repair. Compounds showing inhibitory activities in these experiments will be chosen as candidates for final animal bioassays. In the first year, twenty-one dietary and related compounds have been evaluated for their potential inhibitory activities against the carcinogenic effects of two structurally-related environmental nitrosamines, N-nitrosopyrrolidine (NPYR), and N'-nitrosonornictone (NNN), using in vitro metabolism assays (Stage 1). These in vitro metabolism assays were performed in target tissues of these nitrosamines, namely, rat liver microsomes for NPYR and cultured rat esophagus for NNN. Among these twenty-one tested compounds, which included phenols, cinnamic acids, isothiocyanates, coumarins, and indoles, isothiocyanates have been shown to be the most effective inhibitors. These isothiocyanates will be subsequently assayed in in vivo metabolism and/or DNA adduct formation (Stage 2) and induction of DNA repair assays (Stage 3) during the coming year. The results of these studies (Stage 1 to Stage 3) will allow the selection of the most promising inhibitors for bioassays to be carried out in the third year. The purpose of this supplemental application is to request support for these bioassays. In the bioassays, the two most appropriate inhibitors will be chosen and their inhibitory action against the tumorigenic effects of NPYR and NNN in Fischer 344 rats will be examined. It is crucial that these bioassays be carried out in order to validate the screening methods used in this program and to positively identify new inhibitors of carcinogenesis by nitrosamines.
NIH ExPorter
NIH ExPorter