Human pharmacogenetic traits encompass an array of responses as broad as the effects evoked by exogenous substances in human subjects, a range that is virtually limitless. Outwardly, there is nothing to distinguish a response of hereditary origin from one that is primarily due to environmental causes. Traditionally, the classic principles of genetics applied to twin studies, family studies, and studies in larger populations are employed to differentiate them.
Assignment of a casual relationship between a clinical event and treatment with a specific drug has been based on the evaluation of individual case reports followed by confirmatory epidemiological studies. If the unusual response involves a long lag between exposure and the outright appearance of clinical manifestations, special epidemiological approaches may be necessary to establish the connection between the response and the influence of heredity. Over the short term, this possibility is exemplified by the predisposition of G6PD-deficient individuals to the hemolytic effect of oxidant drugs and over the long term by the predisposition of glutathione-deficient individuals to cancer of the lung and various other tissues.
Methodological difficulties can arise with a disturbing frequency. The usual recourse to the detection of genetic determinants of drug idiosyncrasy involves a combination of classical and molecular genetic approaches to the study of the disposition of the drug in blood, or urine, its rate of elimination, and so on, as already described. Very few tests for genetic susceptibility to the detection of idiosyncratic drug reactions have been designed that protect sensitive individuals from the risk of injury from further exposure as might occur on repeated testing. Noninvasive tests for traits such as for G6PD deficiency and succinylcholine sensitivity avoid the potential for harm because they are performed on samples of blood or serum removed from the test subject prior to testing. Progress has been made toward the development of such techniques through biochemical studies of leukocytes isolated from peripheral blood, and more recently through the application of recombinant DNA technology to the identification of susceptible phenotypes and genotypes, but this area of investigation needs more em-phasis.57
An unusual response to a given exogenous agent may be due primarily to the influence of heredity on the one hand, or to the influence of the environment on the other, but the majority of pharmacogenetic traits fall somewhere between these extremes. Changing environmental exposures and the diverse human genetic composition may make the relative contributions of genetic and environmental factors to the idiosyncrasy difficult or impossible to assess from clinical situations or from epidemiological observations alone. Further complications may arise for responses that result from more than one hereditary element. Although the inheritance of monogenic traits is predictable because it obeys Men-delian rules and Hardy-Weinberg expectations, the inheritance of traits caused by the combination of two or more monogenic traits would not follow Mendelian patterns. This point has been addressed for lupus erythematosus induced by hydralazine,57 and for red blood cell hemolysis induced by sulfones or sulfon-amides.58,59 Other examples of pharmacogenetic importance could arise in connection with responses to therapeutic agents whose actions are mediated by receptor subtypes whose binding specificities overlap, or to carcinogenic chemicals whose metabolism is due to different members of a subfamily of enzymes whose substrate selectivities overlap.
Still further, the extent to which individual responses to certain environmental chemicals or dietary factors60 is affected even within individuals can be quite variable. The controversy of long-standing surrounding the etiological role of heredity versus environment associated with lung cancer in smokers illustrates this point. Despite the potential for genetic susceptibility of humans to this disorder, and a clear relationship between genetically determined differences in metabolic activation of chemical carcinogens by the cytochrome P450 enzyme CYP1A161-63 and susceptibility to cancer in a genetic mouse model, the issue is not completely resolved to everyone's satisfaction.64-69 Another case in point of the latter possibility has arisen in connection with the contentious association of dopamine D2 receptor gene variants with the abuse of cocaine, alcohol, nicotine (in smoking), as well as other chemical dependency syndromes and addictive-compulsive behavioral disorders.70
The determination of the extent and importance of genetically conditioned differences in response to exogenous substances can also be confounded in various ways. For example, Garibaldi's report of an outbreak of isoniazid-induced liver damage with fatal consequences in 1972 drew attention to the extent and severity of this disorder.71 For more than 15 years after that report, investigators debated the origin of this adverse effect and studied the relevance of the human acetylation polymorphism at clinical, epidemiological, and basic pharmacological levels to this problem in patient populations and animal models. As a consequence, we knew that genetic differences in a single metabolic defect in acetylating capacity acted at an early step in the metabolic pathway of isoniazid, and again later. The polymorphic difference in acetylation that converts isoniazid to the hepatotoxin, monoacetylhydrazine, is almost completely blunted by the acetylation of monoacetylhyrazine to diacetylhydrazine; diacetylhydrazine is a nontoxic metabolite that is excreted harmlessly in urine (Figure 5.10). Both ace-tylation steps have a bearing on liver damage, but since the second step opposes the first, and other variable metabolic steps intervene, outright prediction of the effect of acetylator status on isoniazid hepatotoxicity is difficult. During the
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