Historical Overview

Perhaps the first example of an adverse reaction that has a pharmacogenetic basis was described in Southern Italy in 510 B.C. by Pythagoras, who reported that ingestion of fava beans can be harmful to some, but not all, individuals, leading to red cell hemolysis. This was also described with primaquine, an antimalarial drug, in 1956, and related to a deficiency of glucose-6-phosphate dehydrogenase (13). Another classic example reported in the 1950s was the occurrence of prolonged apnea after treatment with suxamethonium in patients with a deficiency of butyrylcholinesterase (14,15). In the 1960s, the occurrence of peripheral neuropathy associated with the intake of isoniazid was related to a deficiency of N-acetylation of the drug in the so-called slow acetylators (16). The first ADR with a P450 polymorphism, the occurrence of hypotension with debrisoquine (17), led to the discovery of CYP2D6 (at that time called debrisoquine hydroxylase). The same genetic defect was later associated with the development of hepatotoxicity and peripheral neuropathy in patients taking the antianginal perhexilene (18,19). Since then, the majority of pharmacogenetic studies of ADRs have concentrated on the role of drug metabolizing enzymes, but with the recent interest in active drug transport, there has also been increasing interest in drug disposition, which may not necessarily be metabolism related. However, it has long been recognized that genes other than those coding for proteins involved in drug disposition, may also predispose to ADRs. For instance, human leukocyte antigen (HLA) has been a focus of interest for many years, perhaps the best example of an association being the higher risk of hydralazine-induced lupus in patients who are HLA-DR4 positive (20,21). Hydralazine-induced lupus also provides an early example of the polygenic nature of the predisposition to ADRs because individuals who are both slow acetylators and HLA DR4-positive have a higher risk than those with one risk factor only (25 out of 26 patients with hydralazine-induced systemic lupus erythematosus (SLE) were slow acetylators) (22).

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