Genetic Mechanisms for Variability in Drug Response and Toxicity

It is now well established that many proteins involved in the metabolism or pharmacodynamic action of drugs and foreign compounds exhibit structural polymorphism and variation in their level of expression. This variation leads to dramatic phenotypic differences in response to medicines or susceptibility to carcinogenesis. Some of the changes in the phenotypic expression of proteins are secondary to variation in the nucleic acid sequence of their respective genes. The science of pharmacogenetics links differences in gene structure (polymorphism) with pharmacologic differences in drug action and disposition of foreign compounds. Through discussion of four examples, we will emphasize the variety of genetic mechanisms that can potentially influence the phenotypic response to xenobiotic challenge and pharmacotherapy. The first example illustrates how structural variation in the coding region of drug metabolizing enzymes influences risk of drug toxicity. A second example demonstrates how genetic variation can influence gene transcriptional regulation and how the resulting dysregulation may be linked to increased susceptibility to exposure-linked cancer. The third example illustrates how genetic polymorphism can selectively influence the pharmacodynamic response to medication, and the final example of warfarin response illustrates how genetic variation in more than one gene can account for broad extremes in phenotypic response.