Genetic heterogeneity and its effect on susceptibility to environmental factors

For many years, human susceptibility to xenobiotics has been known to show wide variations, often on a geographic basis. These insights can be used to identify potentially sensitive populations and provide early prediction of adverse outcomes. A proposed framework to guide the use of such data in risk assessment for vulnerable populations is also presented. Genetic differences play an important role in susceptibility to certain exposures. In the biotransformation process, a xenobiotic undergoes a two-phase process. In the phase I reaction, enzymes from the cytochrome P450 (CYP) family oxidize foreign substances to form high-energy, reactive intermediates. In the phase II reaction, the reactive metabolites are conjugated to form non-reactive, water-soluble molecules that can be more easily transported and excreted from the body. Mutations in the CYP genes may result in an altered metabolism of the xenobiotic substances. Mutations in genes coding for phase II enzymes, such as glutathione S-transferases and N-acetyltransferases, may also lead to decreased catalytic efficiency for the detoxification of a particular xenobiotic and thus increase its toxicity. Several polymorphisms of these enzymes have been implicated for susceptibility to potential chemical carcinogens. These polymorphisms differ in frequencies and in prevalence by geographic distribution. Given its biological significance, genetic heterogeneity and its global variation should be explicitly addressed in conducting risk assessments for vulnerable populations in different regions of the world.