Malaria causes at least 300 million cases of acute illness each year and is the leading cause of deaths in young children. Pregnant women are the main adult risk group in most endemic areas of the world. Malaria is one of the major public health challenges eroding development resources in the poorest countries in the world. Malaria costs Africa more than US$12 billion annually. The potential toxicity of most antimalarials will require special surveillance programs as they will be increasingly used for treatment and prophylaxis. As it is the case with antituberculous medications, there is little knowledge about the molecular basis of drug toxicity or of the genetic markers for prediction of toxicity or treatment efficacy, with the notable exception primaquine.

Primaquine was introduced approximately 50 years ago, and it has long been used for the management of the chronic liver stage of malaria (61). During War World II, primaquine sensitivity was first observed in black soldiers who developed sudden hemolytic reaction after using the 8-aminoquinolone antimalarial drugs. The cause of primaquine sensitivity is now known as a deficiency in the hereditary enzyme glucose 6-phosphate dehydrogenase (G6PD) that causes hemolytic anemia in susceptible individuals after exposure to certain dietary substances, numerous drugs including the 8-aminoquinolones, and also other oxidant chemicals.

The enzyme G6PD is present in most cells and tissues and is responsible for the oxidation of glucose-6-phosphate to 6-phosphogluconic acid. This reaction is necessary to produce NADPH, which functions as a proton donor in the glutathione reductase reaction. Reduced glutathione protects sulfhydryl-dependent enzymes and other cellular proteins against oxidation. Primaquine induces hemolysis by causing further reduction in the level of reduced glutathione in the red cells that already have an impaired mechanism for the regeneration of NADPH. The hemolysis seen in the reduced glutathione-deficient state is the result of increased susceptibility of the erythrocyte to mechanical breakage (62).

The gene that encodes G6PD is located on the long arm of chromosome Xq28 and spans approximately 20 kb with a coding sequence of 1548 bp. Using biochemical techniques, more than 400 variants have been characterized, but only approximately 30 different polymorphims have been identified, almost all of which are found in the coding region (63,64). Two types of mutations are commonly found in Africans: G6PD A and G6PD A-. The first produces normal levels of red cell activity, and the second is unstable and produces only about 10% of the normal activity. G6PD A- is caused due to the substitution of Val to Met at codon 68 (G202 to A) (65). In the African variant G6PD Santamaria, a second mutation (A542 to T) also causes G6PD deficiency. This mutation causes an Asp to Val substitution at codon 181. In Mediterranean individuals, a C563 to T change results in Ser to Phe substitution at codon 188. Little is known about the mutations in Asians than in Mediterraneans, but one of the more common Asians variants, G6PD Canton, has an Arg to Leu substitution at codon 459 (66).

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