Favism: Erythrocyte Metabolism during Haemolysis and Reticulocytosis

Abstract

The reduced activity of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate; NADP+ 1-oxidoreductase; G6PF) in Mediterranean erythrocytes explains the precarious equilibrium of the hexose monophosphate pathway (HMP) and the susceptibility of these cells to haemolytic agents. G6PD-deficient erythrocytes, in steady-state conditions, have a low NADPH/NADP+ ratio, thus allowing the HMP to operate at its maximal intracellular rate and to compensate the intrinsic erythrocyte enzyme deficiency. Studies started soon after accidental intake of fava beans by sensitive G6PD-deficient subjects demonstrate a decrease of both NADPH/NADP+ ratio and reduced glutathione. The metabolic effects induced by fava beans may be attributed to oxidative stress probably associated with an inhibitor effect of some unknown metabolite on the HMP. The availability of erythrocytes from subjects recovering from haemolysis with high reticulocyte counts and increased G6PD activity, provides new information on the rate of synthesis as well as on the in vivo decay of the mutant enzyme. Correlation of G6PD activity to reticulocyte count and extrapolation to an ideally homogenous population of reticulocytes reveal that the mutant enzyme is synthesized at a nearly normal rate. Furthermore, the present correlation allows an estimate of the in vivo half-life of Mediterranean G6PD. The rate of decline of about 8 d observed in this study well correlates to the intracellular metabolic aspects of G6PD Mediterranean erythrocytes.

Predicting the Kinetic Properties Associated with Redox Imbalance after Oxidative Crisis in G6PD-Deficient Erythrocytes: A Simulation Study

“…Such behavior accurately represented the antioxidant mechanism of H 2 O 2 detoxification by G6PD, resulting in depletion of GSH, rapid production of GSSG, and a subsequent decrease of NADPH, as has been shown in previous experiments [33]. The similarity in CAT and GSHpx activity among patients, independent of the degree of deficiency of the G6PD enzyme, agrees with previous observations of normal levels of antioxidant enzymes such as CAT and GSHpx in G6PD-deficient patients, independent of their hemolytic crisis history [34, 35].…”

Catalase: a tetrameric enzyme with four tightly bound molecules of NADPH.

“…Prolonged generation of H202 at low concentrations seems to occur during certain drug-induced peroxidative stresses on erythrocytes (28). Studies of intact erythrocytes in vitro indicate that such stress leads to a moderate decrease of NADH and a severe decrease of NADPH (29,30), the latter resulting from action of the glutathione reductase/peroxidase mechanism (Fig. 3 Lower).…”

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in southeast Iran: implications for malaria elimination

“…G6PD deficiency is most frequently expressed as acute hemolytic anemia and neonatal jaundice, which is usually elicited by external oxidant agents [4]. Exposure to certain medications and chemicals, such as dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride (toluidine blue) [5]; ingestion of fava beans [6][7][8]; topical application of henna [9,10]; and infections [11][12][13], have been reported to trigger hemolytic anemia in G6PD-deficient individuals. Chronic hemolysis associated with some G6PD variants is likely to result in congenital non-spherocytic hemolytic anemia [14].…”