Metabolism of xenobiotics and chemical carcinogenesis

In order to avoid the accumulation of harmful xenobiotics in cells, living organisms have developed ways for their elimination. Multiple xenobiotic metabolizing enzymes with variable but partially overlapping catalytic properties play a key role in the elimination process. These enzymes are encoded by superfamilies of genes which, during the course of evolution, have evolved in a way that has made it possible for the different species to survive and take advantage of different habitats and diet containing a variable composition of harmful xenobiotics. As a result of this evolutionary process, species have achieved capacities to metabolize xenobiotics which are appropriate for their survival but which may differ considerably from those of other species. This evolutionary process may also explain the interethnic and interindividual variability of drug metabolism in humans. Because many carcinogens are substrates of drug-metabolizing enzymes it is reasonable to assume that humans have a variable capacity to activate or inactivate carcinogens. This has been shown to be the case. It appears that most of the carcinogen-metabolizing enzymes are inducible by xenobiotics: they respond to environmental stimuli and therefore vary in their activity. Furthermore, many of the encoding genes are polymorphic and multiple allelic variants relevant for the phenotype may exist in human populations. Analysis of the genetic variability that affects the capacity to metabolize carcinogens in humans has shown that a few members of the cytochrome P450, glutathione S-transferase and N-acetyltransferase gene families may play an Important role in chemical carcinogenesis. Yet for several enzymes such a role has not been established until now, although their catalytic properties and expression in human tissues suggest that such a role should exist. More studies on the role of individual enzymes in chemical carcinogenesis are therefore warranted.