From the Guidelines
Glucose-6-phosphate dehydrogenase (G6PD) is a critical enzyme that protects cells from oxidative damage by generating NADPH, which maintains reduced glutathione levels necessary for detoxifying harmful oxidative species.
Role of G6PD in Cellular Function
G6PD plays a crucial role in cellular function by protecting cells from oxidative damage. The enzyme generates NADPH, which maintains reduced glutathione levels necessary for detoxifying harmful oxidative species. This process is essential for maintaining cellular homeostasis and preventing damage from oxidative stress.
Clinical Implications of G6PD Deficiency
G6PD deficiency, the most common enzyme deficiency worldwide affecting over 400 million people, has significant clinical implications. Patients with G6PD deficiency are at risk for hemolytic anemia when exposed to oxidative stressors such as certain medications (including antimalarials like primaquine, sulfonamides, nitrofurantoin), fava beans, infections, and diabetic ketoacidosis. The severity of hemolysis varies based on the specific genetic variant, with the Mediterranean variant typically causing more severe reactions than the African variant.
Management and Prevention
Management involves avoiding known triggers, prompt discontinuation of offending agents, and supportive care during hemolytic episodes. Clinicians should screen for G6PD deficiency before prescribing high-risk medications, especially in populations with higher prevalence such as those of African, Mediterranean, or Asian descent. Neonatal jaundice may be the first presentation in affected infants. The condition follows X-linked inheritance, making males more commonly and severely affected than females, who may be carriers with variable enzyme activity. According to the most recent study 1, patients with G6PD deficiency may not produce sufficient NADPH to reduce methylene blue to leukomethylene blue, making methylene blue therapy ineffective in these patients.
Some key points to consider:
- G6PD deficiency is a genetic condition that may result in hemolysis after exposure to oxidant drugs 1.
- The severity of hemolysis varies based on the specific genetic variant, with the Mediterranean variant typically causing more severe reactions than the African variant 1.
- Management involves avoiding known triggers, prompt discontinuation of offending agents, and supportive care during hemolytic episodes.
- Clinicians should screen for G6PD deficiency before prescribing high-risk medications, especially in populations with higher prevalence such as those of African, Mediterranean, or Asian descent.
- G6PD deficiency may also be a concern in other medical conditions, such as hyperbilirubinemia in newborns 1 and non-tuberculous mycobacterial pulmonary disease 1.
From the Research
Role of Glucose 6 Dehydrogenase in Cellular Function
- Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway, catalyzing the oxidation of glucose-6-phosphate to 6-phosphogluconolactone, producing nicotinamide adenine dinucleotide phosphate (NADPH) 2, 3, 4.
- The pentose phosphate pathway is a metabolic hub between glycolysis and the pentose phosphate pathway, providing NADPH for several "reducing" biosynthetic reactions 2.
- G6PD is essential for cell survival, as it is a major source of NADPH required by many essential cellular systems, including antioxidant pathways, nitric oxide synthase, NADPH oxidase, and cytochrome p450 system 3.
Clinical Implications of G6PD Deficiency
- Deficiency in G6PD activity can lead to dysregulation of cell growth and signaling, anomalous embryonic development, altered susceptibility to viral infection, and increased susceptibility to degenerative diseases 5.
- G6PD deficiency is associated with neonatal jaundice, drug- or infection-mediated hemolytic crisis, favism, and chronic non-spherocytic hemolytic anemia 5.
- Upregulation of G6PD has been observed in diverse cancers, influencing DNA synthesis, DNA repair, cell cycle regulation, and redox homeostasis, providing advantageous conditions for cancer cell growth, invasion, metastasis, and chemoresistance 4.
Regulation and Inhibition of G6PD
- G6PD is highly regulated by many signals that affect transcription, post-translation, intracellular location, and interactions with other proteins 3.
- Targeting G6PD by inhibitors has been shown as a promising strategy in treating cancer and reversing chemotherapeutic resistance 4.
- The enzymes of the oxidative phase of the pentose phosphate pathway, including G6PD, are targets of reactive species, and their oxidation and inactivation can result in a loss of enzymatic activity and increased oxidative damage due to NADPH depletion 6.