Studies of metabolism mediated mutagenicity in vitro

By Jenssen, D. - Romert, L.

To understand the cause of the biological effects of xenobiotic metabolism in mammals, investigators have traditionally performed animal experiments by comparing the results of biochemical methods, such as measurement of enzyme activity analysis of the metabolites produced, with the observed toxicological effect. This article deals with in vitro methods for genotoxicity combined with drug metabolising preparations at the organelle, cell or organ levels, as exemplified by microsome preparations, isolated cells/cell lines and organ perfusion systems, respectively. The advantage of some of these methods for studying metabolism-mediated mutagenicity is that the measured endpoint reflects not only the bioactivating phase I reactions, but also the detoxifying phase II reactions, and the transfer of the non-conjugated reactive metabolites to other cells and their ability to cause mutations in these cells. In vivo, all these events are important factors in the initiation of cancer. A mechanistic advantage of the methods for metabolism-mediated mutagenicity in vitro is that the relevance of the different steps in metabolism for the mutational events can seldom be investigated in an in vivo assay. Furthermore, human studies can easily be performed using the co-culture technique with isolated human cells or cell lines.