20.5.1 Glucose 6-phosphate Dehydrogenase Deficiency Causes a Drug-Induced Hemolytic Anemia

At its introduction in 1926, an antimalarial drug, pamaquine, was associated with the appearance of severe and mysterious ailments. Most patients tolerated the drug well, but a few developed severe symptoms within a few days after therapy was started. The urine turned black, jaundice developed, and the hemoglobin content of the blood dropped sharply. In some cases, massive destruction of red blood cells caused death.

This drug-induced hemolytic anemia was shown 30 years later to be caused by a deficiency of glucose 6-phosphate dehydrogenase, the enzyme catalyzing the first step in the oxidative branch of the pentose phosphate pathway. This defect, which is inherited on the X chromosome, is the most common enzymopathy, affecting hundreds of millions of people. The major role of NADPH in red cells is to reduce the disulfide form of glutathione to the sulfhydryl form. The enzyme that catalyzes the regeneration of reduced glutathione, the flavoprotein glutathione reductase, a dimer of 50-kd subunits, is homologous to ferredoxin-NADP⁺ reductase, which we encountered in photosynthesis (Section 19.3.4). The reduced form of glutathione serves as a sulfhydryl buffer that maintains the cysteine residues of hemoglobin and other red-blood-cell proteins in the reduced state. Normally, the ratio of the reduced to oxidized forms of glutathione in red blood cells is 500.

How is GSH regenerated from GSSG and NADPH by glutathione reductase? The electrons from NADPH are not directly transferred to the disulfide bond in oxidized glutathione. Rather, they are transferred from NADPH to a tightly bound flavin adenine dinucleotide (FAD) on the reductase, then to a disulfide bridge between two cysteine residues in the enzyme subunit, and finally to oxidized glutathione.

Reduced glutathione is essential for maintaining the normal structure of red blood cells and for keeping hemoglobin in the ferrous state. The reduced form also plays a role in detoxification by reacting with hydrogen peroxide and organic peroxides.

Figure

Vicia faba. The Mediterranean plant Vicia faba is a source of fava beans that contain the purine glycoside vicine. [Inga Spence/ Visuals Unlimited.]

Cells with a lowered level of reduced glutathione are more susceptible to hemolysis. How can we explain this phenomenon biochemically? The presence of pamaquine, a purine glycoside of fava beans, or other nonenzymatic oxidative agents leads to the generation of peroxides, reactive oxygen species that can damage membranes as well as other biomolecules. Peroxides are normally eliminated by glutathione peroxidase with the use of glutathione as a reducing agent (Section 24.4). Moreover, in the absence of the enzyme, the hemoglobin sulfhydryl groups can no longer be maintained in the reduced form and hemoglobin molecules then cross-link with one another to form aggregates called Heinz bodies on cell membranes (Figure 20.25). Membranes damaged by the Heinz bodies and reactive oxygen species become deformed and the cell is likely to undergo lysis. In the absence of oxidative stress, however, the deficiency is quite benign. The occurrence of this dehydrogenase deficiency also clearly demonstrates that atypical reactions to drugs may have a genetic basis.

Figure 20.25

Red Blood Cells with Heinz Bodies. The light micrograph shows red blood cells obtained from a person deficient in glucose 6-phosphate dehydrogenase. The dark particles, called Heinz bodies, inside the cells are clumps of denatured protein that adhere (more...)

20.5.2 A Deficiency of Glucose 6-phosphate Dehydrogenase Confers an Evolutionary Advantage in Some Circumstances

The incidence of the most common form of glucose 6-phosphate dehydrogenase deficiency, characterized by a tenfold reduction in enzymatic activity in red blood cells, is 11% among Americans of African heritage. This high frequency suggests that the deficiency may be advantageous under certain environmental conditions. Indeed, glucose 6-phosphate dehydrogenase deficiency protects against falciparum malaria. The parasites causing this disease require reduced glutathione and the products of the pentose phosphate pathway for optimal growth. Thus, glucose 6-phosphate dehydrogenase deficiency is a mechanism of protection against malaria, which accounts for its high frequency in malaria-infested regions of the world. We see here once again the interplay of heredity and environment in the production of disease.