They are recognized as the cornerstone of the field. Most well-studied polymorphisms derive from investigations of therapeutic agents, because they can be administered safely to individuals of all ages in defined amounts and their disposition patterns can be measured. The enzymes that metabolize exogenous substances may also metabolize hormones and other endogenous messengers that regulate cell signaling, and mutations that affect those pathways may also cause differences in individual responses. The range of such phenomena is virtually without limit.

By the time of Garrod's address in 1914, physiological chemists had already identified most kinds of metabolic reactions of drugs and other exogenous chemicals that we know today. Most of those reactions were identified between 1850 and 1910,3 but the precise dates of their discovery are less relevant to the emergence of modern pharmacogenetics than that they set the stage for unraveling the nature of the enzymes involved in those reactions. In the 1950s, Julius Axelrod at the National Institutes of Health in the United States discovered the subcellular localization of the prime oxidative enzymes and showed them to be responsible for a wide variety of oxidative reactions. These enzymes, now known as the P450 enzymes,4,5 are situated in the endoplasmic reticulum of liver and other tissues. In a much broader look at metabolism, R. Tecwyn Williams, at St. Mary's Medical School in London, authored a compendium of metabolic reactions and proposed the distinction between types of reactions that he termed Phase 1 (oxidation, reduction, and hydrolysis) and Phase 2 (conjugation).6 The designation of Phase 1 and Phase 2 pathways has been widely adopted and is eminently suited for discussions of the biochemical and pharmacological mechanisms of human variation in drug responses.

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