INVITRO SYSTEM FOR DETECTING NONGENOTOXIC CARCINOGENS

Chemical risk assessment has been limited by the inability of in vitro short-term assays to identify the true carcinogenic potential of many substances. Numerous methods exist for identifying mutagenic and clas togenic agents, but a practical means of identifying nongenotoxic carc inogens has remained elusive. Experiments described here suggest that some chemicals may participate in carcinogenesis by modulating the enz ymatic processes of drug metabolism. The tumor promoters butylated hyd roxyanisole, butylated hydroxytoluene, deoxycholic acid, reserpine, tr ypan blue, and 12,-O-tetradecanoyl phorbol-13-acetate were chosen as m odel non-genotoxic carcinogens. The enzyme-modulating action of these chemicals was measured using a modified Ames plate incorporation assay whereby the known tumor promoters were plated with a promutagen in th e presence of a mammalian metabolic activation system (S9). Each of th e nongenotoxic carcinogens significantly increased the mutagenic respo nse of metabolically activated promutagen(s). These experiments sugges t that the carcinogenic role of some chemicals may be attributed to th eir ability to modify the biochemical pathways of drug metabolism. By enhancing or inhibiting the activity of various enzymes, some tumor pr omoters may create an environment that increases a cell's mutational b urden, thereby contributing to neoplastic transformation.