Pharmacogenetic traits

TABLE 8.1. Classic Pharmacogenetic Traits Variation in Biotransformation of Pharmaceuticals... 

Several classic pharmacogenetic traits are listed in Table 8.1 and discussed below. For a variety of reasons, mostly reflecting the slow penetration of genetic thinking into clinical medicine and the limited predictive value of even the best-validated tests, these tests have been significantly underutilized. 

One of the first pharmacogenetic traits to be recognized more than 50 years ago was the slow acetylation of the antituberculosis drug isoniazid now known as the polymorphism of /V-acety11ranslerasc 2 (NAT2) and inherited as an autosomal recessive trait (reviewed in Refs. 11 and 12). 

A pharmacogenetic trait is any measurable or discernible trait associated with a drug, including enzyme activity, drug or metabolite levels in plasma or urine, effects on blood pressure or lipid... 

It is now well accepted that genetic variants affect responses to drugs and chemicals (Kalow, 1965 Bums, 1968). One of the earliest studies in this field compared plasma dmg half-lives in identical and fraternal twin pairs and demonstrated that greater differences existed between the fraternal twins (Vesell and Page, 1968). In recent years, several more monogenic pharmacogenetic traits have been reported (Nebert et al., 2008). One example... 

Polymorphism in the coding part of the genome as well as in the regulatory perigenic regions may be a major factor explaining individual variation of the phenotypes associated with common diseases and with pharmacogenetically determined traits (Housman and Ledley, 1998). For common diseases, the current hypothesis is that relatively common... 

Jones, B.C., Tarantino, L.M., Rodriguez, L.A., Reed, C.L., Mc-Clearn, G.E., Plomin, R., and Erwin, V.G. (1999) Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry. Pharmacogenetics 9 607-617. 

Establishment of definable end-points for the investigation of specific differences between normal and abnormal responders poses another problem. Consider the evaluation of drug treatment of hypertension as a case in point. In this instance, the definitive end-point would be measured by the difference in the incidence of strokes and cardiovascular disease between normal and abnormal drug responders, but this would probably occur years after the trait is recognized and modifying treatment undertaken. Another example of pharmacogenetic interest... 

Genetic factors that influence enzyme levels account for some of these differences. Succinylcholine, for example, is metabolized only half as rapidly in persons with genetically determined defects in pseudocholinesterase as in persons with normally functioning pseudocholinesterase. Analogous pharmacogenetic differences are seen in the acetylation of isoniazid (Figure 4-5) and the hydroxylation of warfarin. The defect in slow acetylators (of isoniazid and similar amines) appears to be caused by the synthesis of less of the enzyme rather than of an abnormal form of it. Inherited as an autosomal recessive trait, the slow acetylator phenotype occurs in about 50% of blacks and... 

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