SEVERE PLASMODIUM FALCIPARUM MALARIA IN CAMEROON: ASSOCIATED WITH THE GLUTATHIONE S-TRANSFERASE M1 NULL GENOTYPE

Glutathione S-transferases (GST) are a family of enzymes involved in phase-II detoxification of endog- enous and xenobiotic compounds. Polymorphisms in GST genes have been associated with susceptibility to different diseases. In this study we determined the frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1 in DNA of 138 children from Cameroon, presenting with uncomplicated malaria (N 19), malaria with minor complications (N 81), or severe malaria (N 38). Analyses of GSTM1 and GSTT1 were performed using PCR-multiplex procedure, while GSTP1 was done by PCR-RFLP. Subjects presenting with malaria with complications were found more often of the GSTM1-null genotype (58-64%) as compared with those with uncomplicated malaria (32%), a difference that was statistically significant. We conclude that the GSTM1-null genotype is associated with malaria with complications. In severe malaria, release of oxygen free radicals and a variety of pro-inflammatory cytokines can lead to increased vascular permeability, leakage of colloid from intravascular space, pathologic vasodilation, and myocardial depression with ultimate hypovolemia and impaired organ perfusion. In children with malaria, lipid peroxidation in both blood plasma and erythrocytes is increased, while erythrocytic antioxidants such as glutathione (GSH), catalase, and tocopherol were shown to be lower in patients with malaria than in control subjects. 1 The intracellular parasite digests hemoglobin, thereby releasing free ferroprotoporphyrin or heme, which in the presence of oxygen oxidizes to ferriprotoporphyrin or hemin. This process produces superoxide, which decomposes into H2O2 and O2. Antimalarials like chloroquine and amo- diaquine inhibit this reaction, thus building up a toxic con- centration of ferro/ferriprotoporphyrin (FP) leading to para- site death. 2,3 Indeed, several studies have suggested that an increase in oxidative stress in parasitized red blood cells (RBCs) offers an advantage to parasite clearance rather than exacerbating the pathology. 2-4 Glucose-6-phosphate dehy- drogenase (G6PD)-deficient individuals for instance, are par- tially protected against malaria. G6PD is essential for NADPH production, which reduces oxidized glutathione. Glutathione as an antioxidant is required for growth of the parasite 2,5 but also for maintenance of the redox state of the host cell. Altered redox metabolism of the host cells, particu- larly the endothelial cells, may exacerbate disease complica- tions, for example by enhancing endothelial damage, brain inflammation, and development of cerebral malaria. Several studies document escape of FP from the parasite's food vacu- ole with consequent damage to erythrocyte membrane through oxidation of proteins and lipids with eventual lysis of the host cell. 6-8 To maintain the integrity of the erythrocyte