Glucose-6-Phosphate Dehydrogenase
Phenotypes demonstrating variations in people's response to certain drugs were first discovered in the early 1950s when antimalarial drugs were found to cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD, expressed in all of the body's tissues, controls the flow of carbon through the pentose phosphate pathway, produces NADPH for reductive biosynthesis, and maintains oxidation-reduction in the cell to keep glutathione in a reduced state.[7,8] The absence of reduced glutathione due to G6PD deficiency allows oxidative drugs to oxidize sulfahydroxyl groups of hemoglobin, leading to hemolysis. Currently, over two dozen drugs, including primaquine, sulfones, sulfonamides, nitrofurans, vitamin K analogues, cefotetan, and chloramphenicol, are known to cause hemolytic anemia in G6PD-deficient patients. G6PD deficiency is a sex-linked (chromosome X) recessive trait and a widespread polymorphism, with more than 400 known variants and affecting more than 400 million people worldwide. However, the vast majority of affected individuals are asymptomatic. Only 30 different functional mutations in the gene have been reported, virtually all of which are found in the region of the gene that codes for the protein.[9,10] All but one are point mutations, with more than 50% being nucleotide conversions from cytosine to guanine.[11] The consequence of these genetic polymorphisms is low G6PD activity, resulting in reduced glutathione concentrations in erythrocytes and subsequently clinical manifestation of hemolytic anemia following the ingestion of certain drugs.[12]
The prevalence of G6PD deficiency differs among ethnic groups. For instance, males of African and Mediterranean descent more frequently express the trait. Two types of mutations are commonly found in Africans, G6PD A and G6PD A(-). The former protein produces normal red cell activity, while the latter produces only about 10% of the normal activity and is unstable in vivo. In patients with G6PD A, an adenosine-to-guanine substitution at nucleotide 376 (A376G) mutation causes an aspartic acid residue to replace an asparagine residue.[13] There are three different G6PD A(-) variants in one allele. The A376G mutation occurs in all people, but the enzyme deficiency is caused by a second amino acid substitution, usually a G202A mutation, resulting in a valine-to-methionine substitution at codon 68 (Val68Met). Other mutations are Val690Met and Val968Met. In Mediterranean peoples, the most common mutation is a C563T substitution resulting in an amino acid change (Ser188Phe).
Cases of drug-induced hemolytic anemia have also been described in patients treated with cyclosporine, tacrolimus, penicillin, and cefotetan.[14] The risk and severity of hemolysis are thought to be associated with dose, duration of therapy, and other oxidant stresses, such as infection and environmental factors. Because of these confounding factors, genotyping patients for G6PD deficiency is not warranted, since the toxicity is rare and not typically life-threatening and the genotype does not adequately predict the development of hemolytic anemia. For example, some patients with these mutations experience toxicity after drug administration, and others do not. In addition, the treatment for drug-induced oxidative hemolytic anemia is merely cessation of drug administration, with blood transfusion and corticosteroid administration warranted in severe cases.
G6PD deficiency is an example of how genotypic analysis was developed about half a century after the clinical observation was made, and further characterization of the genetic mutation provided no added clinical advantages. Although genetic constitution may be at the core of explaining drug toxicity and efficacy, genotyping may not always directly affect therapy or predict patient outcomes.
Am J Health Syst Pharm. 2002;59(21) © 2002 American Society of Health-System Pharmacists
Cite this: Genetic Basis of Drug Metabolism - Medscape - Nov 01, 2002.
