We hear almost every day about the unwanted effects of prescription drugs and over-the-counter nostrums, of unsafe substances in foods, and of the perils of tobacco smoking and drinking alcohol. We cannot help but wonder why such effects occur in only a fraction of persons exposed, or why a drug that is therapeutic in one person may be ineffective, or even toxic, in another. This is the province of pharmacology. During the period in and around the 1950s, pharmacologists demonstrated, contrary to common belief, that adverse responses accompanying exposure to exogenous substances were closely tied to a person's genetic makeup (Figure 1.1). When this concept was proposed, it was not entirely new because biologists had long understood that the capacity of organisms to respond differently to the environment was genetically determined. Even so, demonstrating that heredity exerted important effects on human drug responsiveness was an innovative step that cast doubt on the notion that the drug recipient was merely a passive bystander in this process.

Before 1950, few specifics were known about the effects of heredity on such responses, but then the potential significance of genetic differences to the safe, effective use of drugs and the unusual hazards posed by other environmental chemicals began to attract more and more attention from the biomedical community. Recently, the flourishing of genomics has changed the focus of phar-macogenetics from the effects of single genes, addressed one at a time, to the effects of a rich variety of functional elements that affect variation in the expression of many genes.

The periods in and around the 1950s and the year 2000, capped by the discovery of the DNA double helix and the maturation of the human genome initiative, respectively, were periods of remarkable achievement in the quest for knowledge of heredity. These periods tend to overshadow the time of earlier discoveries that led to the inception of modern genetics and pharmacogenetics. For a more balanced perspective on the evolution of pharmacogenetics, we turn to the middle of the nineteenth century, from which time the foundations of pharmacology and

Personalized Medicine

Personalized Medicine

New Gene-Based Drugs

Discovery of genetic variation in liver enzymes

Discovery of genetic variation in liver enzymes

G Early Genetics

D Emergence of Modern Genetics and Pharmacogenetics G The Genomics Era

Figure 1.1 Landmarks in pharmacogenetics.

genetics, stretching to the present, can be divided into roughly four periods (Table 1.1). The first two periods, which extend from 1850 through the end of the second period to about 1960, define the cellular and molecular foundations of early pharmacology and genetics, while the last two periods address events from about 1960 to the present and define the informational and genomic foundations of modern biology and pharmacogenetics.

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