A branch of glucose metabolism, parallel to glycolysis, where glucose-6-phosphate is diverted to produce cellular NADPH and ribose-5-phosphate; metabolites important in redox homeostasis, nucleotide and fatty acid synthesis. Due to loss of hemoglobin O2 binding, symptoms are largely related to O2 deficiency. An endogenous antioxidant that protects the cell from oxidative stress by neutralizing ROS; upon reaction with ROS, GSH is converted to GSSH, where it is recycled back into GSH by glutathione reductase, using NADPH as a cofactor.
What are G6PD deficiency symptoms?
You should also avoid eating fava beans while breastfeeding if your newborn has a G6PD deficiency. The compounds that can trigger hemolytic anemia can travel through breast milk. G6PD is important because it prevents too many “free radicals” from building up in your red blood cells. Free radicals are usually harmless substances found in all kinds of places, like the environment, fava beans and medicines. Currently, Tecfidera® (dimethyl fumarate), indicated for use in multiple sclerosis, is the only FDA approved activator of Nrf2.
What questions should I ask my healthcare provider?
Left untreated, infants with severe jaundice can develop brain damage (kernicterus). This is why your healthcare provider will test your newborn for G6PD deficiency if they suspect they have it. In erythrocytes, the absence of mitochondria limits the contribution of IDH1 and ME1. Although erythrocytes lack mitochondria, they still express TCA cycle enzymes as well as IDH1 and ME1 76 and are capable of metabolizing TCA intermediates to generate NADPH. Precursors of complementary routes have been found to accumulate in G6PDdef erythrocytes, suggesting ME1 and IDH1 pathways are activated to maintain NADPH levels 64. However, this is insufficient to counteract erythrocytes vulnerability to oxidative stress in G6PDdef.
Generation of NADPH via Complementary Pathways
D) Once inside, DHA is reduced by GSH, depleting the already small GSH pool in G6PDdef. E) The ascorbate, imported from the plasma or generated via DHA reduction, can interact with oxidized iron to generate radicals. F) Both GSH depletion and iron-generated radicals likely contribute to cell damage and a hemolytic phenotype in G6PDdef. High glucose levels inhibit G6PD activity and increases oxidative stress 33. Glucose-mediated G6PD inhibition reduced insulin secretion from ß-islets and induced ß-cells apoptosis, with overexpression of G6PD rescuing high glucose mediated dysfunction 34. Additionally, glucose-mediated G6PD inhibition resulted in elevated ROS in podocytes resulting in podocyte injury 33, a complication of diabetes that can lead to diabetic kidney disease 35.
A recent genome-wide CRISPR screen identified loss of G6PD function as synthetic lethal when combined with mitochondria dysfunction 42, a known contributor to the pathogenesis and pathophysiology of neurodegenerative disorders 43. If you have G6PD deficiency, certain medications can trigger severe health issues. Discover which drugs to avoid and why it matters for your well-being. When these symptoms develop fast and are severe, it’s called a hemolytic crisis. Seek emergency care if you’re experiencing signs of a hemolytic crisis. A cofactor that is used for biosynthetic reactions and plays a major role in protecting the cell against oxidative stress.
Neurodegenerative Disorders
Recently, we sought a structural chaperone that could correct the most common variants and identified one lead compound, AG1. AG1 improved the activity and stability of several Class II and Class III variants, including the common Mediterranean and A− and Canton, by stabilizing dimeric G6PD in vitro, in cellulo, and in vivo models 101. As a result, AG1 increased NADPH and GSH levels, reduced ROS, and protected cells from oxidative stress. A) Ascorbate concentration increases in the plasma as a result of IV or oral administration. B) In the presence of oxidative stress, ascorbate is oxidized to DHA in the plasma. C) Subsequently, DHA and ascorbate are imported into erythrocytes, with DHA having a higher preference for import.
Seek immediate medical help if your symptoms are severe and come on quickly (signs of a hemolytic crisis). Healthcare providers use different treatments based on the situation. For example, if you have mild jaundice and your provider knows you have G6PD deficiency, they’ll treat your jaundice symptoms first. Then, they’ll tell you what triggers you need to avoid going forward. Whereas NADPH-dependent GSH regeneration is one way by which the GSH pool can be restored, other metabolic pathways are capable of generating GSH.
Astaxanthin, a lipid soluble carotenoid pigment, increased the activity of purified G6PDWT in a dose-dependent manner, with a maximum 30% activation achieved at 0.64 mM astaxanthin, suggesting a direct mechanism 59. Other carotenoids have been shown to exert antioxidant effects in erythrocytes in vivo, though they did not protect against GSH depletion 60,61. In some cases, alternative medications can be used safely for those with G6PD deficiency. For example, vitamin C may be used instead of methylene blue to treat methemoglobinemia. Always discuss with a healthcare provider to find suitable alternatives that don’t pose a risk of hemolysis. See your healthcare provider any time you develop G6PD deficiency symptoms.
Natural products such as curcumin, sulforaphane, and flavonoids have also been shown to activate Nrf2 94,95. Unfortunately, these molecules are electrophiles and lack target specificity, making them toxic 96,97. A small molecule or peptide inhibitor of the Keap1/Nrf2 protein interaction may increase target selectivity and overcome toxicity and remains an attractive target 98. As with all drugs, too much of anything can be a bad and chronic activation of Nrf2 may cause reductive stress 93.
- Ascorbate, more commonly known as vitamin C, is a potent antioxidant; however, it has prooxidant effects in human erythrocytes in vivo 44 and high-dose ascorbate (e, g., ≥ 6mg/day 45) induces AHA in G6PDdef individuals (Table 1).
- Additionally, treatment with α-tocopherol appeared safe at the indicated doses, suggesting that AHA is not a common feature of antioxidants.
- When these symptoms develop fast and are severe, it’s called a hemolytic crisis.
- If you have G6PD deficiency, certain medications can trigger severe health issues.
- As with all drugs, too much of anything can be a bad and chronic activation of Nrf2 may cause reductive stress 93.
Ask your healthcare provider for information to help you manage the impact G6PD deficiency has on your life. If you have severe hemolytic anemia, you may need a blood transfusion. If your newborn has jaundice, their provider may treat it with phototherapy (a natural or artificial light treatment). For this procedure, the provider removes your baby’s unhealthy blood and replaces it with healthy, donated blood. G6PD medications G6PD deficiency is a genetic disorder that causes your G6PD levels to be too low. G6PD (glucose-6-phosphate dehydrogenase) is an enzyme that protects your red blood cells from injury.
Despite this, lower doses have been used to treat methemoglobinemia in G6PDdef patients (Table 1) 23,46-48; four case studies reported use of ascorbate to treat methemoglobinemia induced by rasburicase or other AHA triggers (Table 1). However, blood transfusions were used as co-treatments, masking the safety and efficacy profile of low-dose ascorbate. A combination therapy including oral NAC and a GCL activator, the rate limiting enzyme of GSH biosynthesis, may improve GSH levels in erythrocytes, protecting them against oxidative stress.
- Your healthcare provider can best explain what to expect based on your diagnosis.
- A recent genome-wide CRISPR screen identified loss of G6PD function as synthetic lethal when combined with mitochondria dysfunction 42, a known contributor to the pathogenesis and pathophysiology of neurodegenerative disorders 43.
- In G6PDdef patients, α-tocopherol improved hematological parameters (Table 2); it increased erythrocyte half-life (from 23 to 25 days), Hb levels, and reduced reticulocytosis in the most severe Class I and II G6PDdef 54-56.
- A second molecular target of interest is transcription factor nuclear erythroid receptor 2 (Nrf2).
However, despite its reputable role as a therapeutic antioxidant, few cases report the use of NAC to treat G6PDdef (Table 2). G6PDdef is a major and well-known risk factor for jaundice and hyperbilirubinemia in newborns as hemolysis increases bilirubin levels in the serum 28. In newborns, bilirubin can cross the blood brain barrier and cause neurological issues such as kernicterus or acute bilirubin encephalopathy 29. Interestingly, newborns with kernicterus have a higher chance of developing sensorineural hearing loss 30, suggesting a role of G6PDdef in auditory disorders.
Though, this may present challenging since drugs that cause AHA in vivo may not translate in vitro. A surrogate endpoint may reduce the duration length and cost of clinical trials and be a better indicator of drug efficacy with hematological indices better served as secondary endpoints. Additionally, animal models of G6PDdef may serve as good preclinical models for testing safety and efficacy of new therapeutics; zebrafish, mouse, and C. Ascorbate, more commonly known as vitamin C, is a potent antioxidant; however, it has prooxidant effects in human erythrocytes in vivo 44 and high-dose ascorbate (e, g., ≥ 6mg/day 45) induces AHA in G6PDdef individuals (Table 1).