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Human erythrocytes with deficient glucose-6-phosphate dehydrogenase levels are unable to maintain their levels of reduced glutathione in the presence of low-level, steady-state concentrations of hydrogen peroxide. This finding has bearing on the biochemical mechanisms of drug-induced hemolytic anemia.
Erythrocyte G6PD from 1157 nondeficient Thai males was studied electrophoretically. The enzyme from four subjects showed abnormal mobility. Characterization of the enzyme revealed three new variants: G6PDs Ayutthaya (n = 2), S-Sakorn, and Chao Phya.
Two thousand people on the Isles of the Baleares were screened for glucose-6-phosphate dehydrogenase deficiency using a commercially available kit. Among the thousand males tested, five were found deficient; of the thousand women, one had low enzyme activity according to this test. Diagnosis of glucose-6-phosphate dehydrogenase deficiency could be verified using hair follicle analysis on mailed hair samples. The same technique also allowed heterozygotes to be identified unequivocally.
A decreased level of glucose-6-phosphate dehydrogenase might result from decreased rate of synthesis, synthesis of an enzyme of lower catalytic efficiency, increased lability, or a combined mechanism. To test the hypothesis of increased lability, the rate of decline of the enzyme in vivo was measured in three groups of individuals, controls, Gd(-),A-males, and Gd(-), Mediterranean males, by the slope of decline of activity in fractions containing erythrocytes of progressively increasing mean age. These fractions were obtained by ultracentrifugation on a discontinuous density gradient of erythrocyte suspensions free of contaminating platelets and leukocytes. The rate of in vivo decline of pyruvate kinase (another age-dependent enzyme) was also measured and found very similar in the three groups. The in vivo decline of glucose-6-phosphate dehydrogenase was found to follow an exponential rate, with a half-life of 62 days for controls and 13 days for Gd(-),A- erythrocytes. The activity in normal reticulocytes was estimated at 9.7 U and in Gd(-),A- reticulocytes at 8.8 U. These estimates were confirmed by direct measurements in reticulocytes isolated from patients with extreme reticulocytosis. In Gd(-),Mediterranean erythrocytes activity could be demonstrated only in reticulocytes, which were estimated to average 1.4 U. The rate of decline is so extreme that no activity could be detected in mature erythrocytes. These data suggest that the glucose-6-phosphate dehydrogenase deficiency of both the Gd(A-) and the GdMediterranean variant results from different degrees of in vivo instability of the abnormal enzyme.
The behaviour of serum haemopexin was studied in patients with hyperhaemolysis after ingestion of fava beans. The linear increase in this substance after a crisis is particularly emphasized. This finding is of special importance for G-6-PD subjects with various haematological disorders.
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Saliva was investigated for its suitability as a biopsy tissue for the determination of glucose-6-phosphate dehydrogenase deficiency. It appears that there is a significant difference between the activity of the enzyme in patients and controls. However, some controls have very low values making discrimination between patients and controls using a qualitative method impossible. Glucose-6-phosphate dehydrogenase deficiency is a relevant clinical problem in many rural areas in developing countries. Existing methods for determination of the deficiency in blood and hair follicles do not meet the criteria necessary for their large scale introduction in the areas of the world that are concerned by the problem. The present study shows that saliva is not a suitable alternative. Between the three biopsy tissues compared: blood, hair follicles and saliva, hair follicles remain most attractive since their isolation hardly involves the risk of infection. A simplified method for the detection of glucose-6-phosphate dehydrogenase activity in hair follicles that would allow health service workers in the field to determine the carrier status of pregnant women might form the basis for a future kernicterus prevention programme.
Erythrocytes of 145 sheep representing six breeds were assayed for glucose-6-phosphate dehydrogenase. All sheep had erythrocyte glucose-6-phosphate dehydrogenase values similar to glucose-6-phosphate dehydrogenase deficient erythrocytes of man. Mean erythrocyte glucose-6-phosphate dehydrogenase levels ranged from 0.65 to 1.54 micromoles of reduced nicotinamide adenine dinucleotide phosphate per gram of hemoglobin per minute. Many of these sheep also had low levels and/or unstable reduced glutathione. Sheep with low levels of erythrocyte glucose-6-phosphate dehydrogenase and reduced glutathione were given large doses of oxidizing drugs or fed fresh fava beans to determine if they would develop intravascular hemolysis. No significant hemolysis was detected as a result of drug administration or fava bean ingestion.
69 out of 2,304 Vietnamese males were found to be hemizygous carriers of the Gd- gene. The glucose-6-phosphate dehydrogenase (G6PD) deficiency had a polymorphic frequency in the Vietnamese population (0.0299). Genetic heterogeneity in G6PD was found - 3 G6PD variants were found among 13 G6PD-deficient males studied (G6PD Canton, G6PD Hanoi and G6PD Vin Fu). Two new variants were identified - G6PD Hanoi and G6PD Vin Fu.
Methylene blue continues to be used in the gravid female. We report three premature neonates exposed to methylene blue that experienced severe hemolytic reactions requiring exchange transfusions. Two neonates were subsequently diagnosed with G6PD deficiency. Continued caution is warranted prior to the use of methylene blue in the gravid female.
Preeclampsia is partially attributed to lipid peroxidation of the syncytitrophoblast plasma membranes (SPMs). Peroxidation of the SPMs could be augmented when the capacity of the cells to produce antioxidant molecules is diminished. One of the most important antioxidant molecules that protects the SPMs is the reduced glutathione (GSH). The latter is produced in the pentose phosphate pathway that requires normal activity of glucose 6 phosphate dehydrogenase (G6PD). Therefore, it is hypothesized that pregnant women with G6PD deficiency are at higher risk for development of preeclampsia than those with normal G6PD activity. Deficiency of this enzyme leads to the deficiency of reduced GSH which is required to protect SPMs against lipid peroxidation and the consequent obstetric morbidity.
Band 3 modifications that normally occur during physiological red blood cell (RBC) senescence in humans, and occasionally in pathological conditions are described in the context of their role in enhancing RBC recognition and phagocytic removal. Band 3 modifications are mostly due to oxidative insults that gradually accumulate during the RBC lifespan or impact massively in a shorter time period in pathological conditions. The oxidative insults that impact on the RBC, the protective mechanisms that counteract those damages and the phenotypic modifications that accumulate during the RBC lifespan are described. It is shown how specific oxidative as well as non-oxidative band 3 modifications enhance RBC membrane affinity for normally circulating anti-band 3 antibodies, and how membrane-bound anti-band 3 antibodies bring about a limited complement activation and membrane deposition of complement C3 fragments. The partially covalent complexes between anti-band 3 antibodies and complement C3 fragments are very powerful opsonins readily recognized by the CR1 complement receptor on the phagocyte. Band 3 modifications typically encountered in old RBCs have crystallized to a number of band 3-centered models of RBC senescence. One of those band 3-centered models, the so-called 'band 3/complement RBC removal model' first put up by Lutz et al. is discussed in more detail. Finally, it is shown how the genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) plus fava bean consumption, and a widespread RBC parasitic disease, P. falciparum malaria, may lead to massive and rapid destruction of RBCs by a mechanism comparable to a dramatic, time-compressed enhancement of normal RBC senescence.
6,366 Afro-American infants were screened for G6PD activity. 379 males (11.4%) and 77 females (2.5%) were deficient. Confirmation was made by a standard spectrophotometric assay. The results for the male infants in this study are comparable to those found in other studies which accurately establish the deficient male.
A solid-phase radioimmunoassay for human glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP+ 1-oxidoreductase; EC 1.1.1.49) was developed that allowed the specific activity of this enzyme protein to be measured in lysates from whole erythrocyte populations, in lysates from erythrocytes of different ages, and in purified samples. The enzyme was highly purified from erythrocytes of single donors by a simple procedure of affinity chromatography with insolubilized adenosine 2',5'-bisphosphate. These techniques were used in an attempt to elucidate the molecular mechanisms leading to deficiency of glucose-6-phosphate dehydrogenase activity in two genetic variants of the enzyme, i.e., the Mediterranean and the Seattle-like variants. The results indicate that the lowered activity of erythrocytes containing the Mediterranean variant of glucose-6-phosphate dehydrogenase is related to an enhanced rate of degradation of a catalytically defective protein synthesized at a nearly normal rate. Synthesis of a normally functioning protein and an increased breakdown of it are involved in the Seattle-like variant of the enzyme.
Modern techniques of molecular biology have made it possible to identify mutations in a number of different hereditary red cell enzyme defects. Most of the studies have been performed in glucose-6-phosphate dehydrogenase deficiency, where a large number of point mutations have been identified. The same mutations are encountered repeatedly, even in patients with defects that were thought, on the basis of biochemical properties of the residual enzyme, to be distinct. A beginning has been made in identifying mutations in a few other red cell enzyme defects.
Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase exhibit an 85% decrease of this enzymatic activity. There is a 26% and a 94% decrease of the hexose monophosphate shunt and of the reduced nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate ratio, respectively. Incubation with 0.1 mM methylene blue activates the hexose monophosphate shunt 7 times that of normal fibroblasts and only 2.2 times that of glucose 6-phosphate-deficient cells. This behavior is coupled with an increase of the resistance to cell death induced by benzo(a)pyrene, a carcinogen, the activation of which proceeds through a reduced nicotinamide adenine dinucleotide phosphate-dependent arene oxide formation. In contrast, no difference between the normal and the deficient fibroblasts exists as regards the toxic effect of methylnitrosourea, a carcinogen that does not need metabolic activation. A growth-retarding effect of benzo(a)pyrene was observed in both normal and deficient cells during 9 days in vitro. This effect is lower in the fibroblasts carrying the Mediterranean glucose-6-phosphate dehydrogenase variant. Glucose-6-phosphate dehydrogenase deficiency protects human fibroblasts against the benzo(a)pyrene-induced in vitro transformation. This effect is mimicked by the incubation of normal fibroblasts with dehydroepiandrosterone, a strong inhibitor of glucose-6-phosphate dehydrogenase. The deficiency of this enzymatic activity, either genetically transmitted or induced by dehydroepiandrosterone, is coupled with a reduced rate of benzo(a)pyrene conversion to water-soluble metabolites by human skin fibroblasts.