Metabolic polymorphisms and cancer susceptibility.
The vast majority of cancers arise as a consequence of exposure to environmental agents that are toxic or mutagenic. In response to this, all higher organisms have evolved complex mechanisms by which they can protect themselves from environmental challenge. In many cases, this involves an adaptive response in which the levels of expression of enzymes active in the metabolism and detoxification of the foreign chemical are induced. The best characterized of these enzyme systems are the cytochrome P450s, the GSTs and the NATs. An unfortunate consequence of many of these reactions, however, is the creation of a toxic or mutagenic reaction product from chemicals that require metabolic activation before realizing their full carcinogenic potential. Altered expression of one or more of these drug metabolizing enzymes can therefore be predicted to have profound toxicological consequences. Genetic polymorphisms with well defined associated phenotypes have now been characterized in P450, GST and NAT genes. Indeed, many of these polymorphisms have been associated with decreased or increased metabolism of many tumour promoters and chemical carcinogens and hence offer protection against or increased susceptibility to many distinct tumour types.