This paper is available online at http://dmd.aspetjournals.org The topic of genetic profiling in patient care was recently reviewed in Nature Biotechnology under the title "Laying the foundations for personalised medicines" Genetic variability and selection directed toward the characters of the individuals are considered to be the fundament of the evolution and adaptation of living organisms to all environments where they are able to exist. The interplay between genetic constitution and other factors has consistently been emphasized. The true meaning of "heritage" is sometimes misunderstood. The fact that a character is inherited or has a genetic predisposition does not mean that it has to penetrate into the phenotype of the next generation or that parents necessarily need to share a quality that is obvious in their children. Many characters may be conceived as continuous variables, and among these are diverse physical and intellectual capacities, talents for art, etc. However, they all go back to the genetic code and will only appear as continuous or even gaussian variables if a large enough number of factors is involved in their control and a large enough number of individuals is studied. When investigated in detail, however, most characters will show skewness or separation into different modes. This can be explained by the influence of particularly strong factors such as monogenic or oligogenic coding systems or the influence of singular environmental factors. Many examples of characteristics such as eye color, blood groups, tissue antigens, etc. show discrete variation into separate groups. This is also true for certain drug-metabolizing enzymes. An early observation was that isoniazid might be slowly or rapidly acetylated The most important drug-metabolizing enzyme family is the cytochrome P450 system. It comprises several enzymes that show distinct but partially overlapping substrate specificity Tricyclic antidepressants were early found to display vast interindividual variability in steady-state plasma concentrations. The Debrisoquine/Sparteine Hydroxylation Polymorphism (CYP2D6) Debrisoquine was launched as an antihypertensive agent but is no longer on the market. It was found to induce orthostatic hypotension in a small percentage of healthy volunteers who took the drug for investigational purposes. The reason for the exaggerated effect in these subjects was found to be the lack of an enzyme almost exclusively responsible for the metabolic elimination of debrisoquine, and the affected subjects were classified as poor metabolizers of debrisoquine The character of being a poor (PM) or an extensive metabolizer (EM) of debrisoquine is controlled as an autosomal, recessive monogenic trait with the PM phenotype being the recessive alternative. The genetic heritability of the debrisoquine hydroxylation phenotype is very high (79%), while only 6% of all variability of the debrisoquine metabolic ratio could be ascribed to environmental or cultural factors (Steiner et al.
