Direct or proximate contact between cells and metabolic activation systems is required for mutagenesis

Abstract

THE adverse biological effects of most carcinogens and/or mutagens are dependent on the formation of electrophilic intermediates which react with nucleophilic groups in cellular macromolecules. Inclusion of a metabolic activation system in various assays enables the detection of mutagenic activity for carcinogens and/or mutagens which require such metabolic activation. In mutagenesis assays, using mammalian cells, two metabolic activation systems have been used: cell-mediated mutagenesis (CMM), in which cells are co-cultured with metabolically competent, but lethally irradiated, cells (feeder layer)^1,2, and microsome–mediated mutagenesis (MMM), in which cells are treated with chemicals in the presence of a microsomal fraction from rodent livers and an NAPDH–generating system^3–5. The present study was carried out in order to investigate whether direct or proximate contact between target cells and such mediators of metabolism is necessary for the induction of mutagenesis. The results suggest that such contact is essential in both cell- and microsome-mediated mutagenesis of mammalian cells and, possibly, also in bacterial systems.