Smith G, Stanley L A, Sim E, Strange R C, Wolf C R
Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee.
Cancer Surv. 1995;25:27-65.
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.
绝大多数癌症是由于接触有毒或致突变的环境因子而引发的。对此，所有高等生物都进化出了复杂的机制来保护自身免受环境挑战。在许多情况下，这涉及一种适应性反应，即诱导参与外源化学物质代谢和解毒的酶的表达水平。这些酶系统中研究得最清楚的是细胞色素P450、谷胱甘肽S-转移酶（GST）和N-乙酰转移酶（NAT）。然而，许多这些反应的一个不幸后果是，一些化学物质在充分发挥其致癌潜力之前需要代谢激活，而这些反应会产生有毒或致突变的反应产物。因此，可以预测这些药物代谢酶中一种或多种的表达改变会产生深远的毒理学后果。现已在细胞色素P450、GST和NAT基因中鉴定出具有明确相关表型的基因多态性。事实上，许多这些多态性与许多肿瘤启动子和化学致癌物的代谢减少或增加有关，因此对许多不同类型的肿瘤提供保护或增加易感性。
