Gene-Nutrient Interactions in G6PD-Deficient Subjects – Implications for Cardiovascular Disease Susceptibility

Background/Aims: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingeste...

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Published inJournal of nutrigenetics and nutrigenomics Vol. 1; no. 1-2; pp. 49 - 54
Main Authors Muntoni, Sergio, Muntoni, Sandro
Format Journal Article
LanguageEnglish
Published Basel, Switzerland 01.01.2008
Subjects
Online AccessGet full text
ISSN2504-3161
1661-6499
2504-3188
DOI10.1159/000109874

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Abstract Background/Aims: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingested by G6PD-deficient subjects (gene-nutrient interaction), or some oxidant drugs are assumed (gene-drug interactions), a life-threatening hemolysis can occur. However, the same defect results in lower cardiovascular disease (CVD) risk. Methods: Physiopathological, clinical and mortality studies of CVD risk in relation with G6PD deficiency have been surveyed. Results: CVD risk in men was lowered in the G6PD-deficient state, and was associated with reduced levels of plasma low-density lipoprotein cholesterol (LDL-C) compared to the normal condition (p < 0.05). Both cholesterol and DNA synthesis in circulating mononuclear cells from G6PD-deficient men were likewise reduced (p = 0.05). Conclusions: Since NADPH is a necessary cofactor for the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R), G6PD deficiency appears to be a naturally occurring model of HMG-CoA R restraint, whose consequences are similar to those produced on the same enzyme by statins. G6PD deficiency therefore results in protection against CVD, despite an increased susceptibility to oxidative stress.
AbstractList Background/Aims: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingested by G6PD-deficient subjects (gene-nutrient interaction), or some oxidant drugs are assumed (gene-drug interactions), a life-threatening hemolysis can occur. However, the same defect results in lower cardiovascular disease (CVD) risk. Methods: Physiopathological, clinical and mortality studies of CVD risk in relation with G6PD deficiency have been surveyed. Results: CVD risk in men was lowered in the G6PD-deficient state, and was associated with reduced levels of plasma low-density lipoprotein cholesterol (LDL-C) compared to the normal condition (p < 0.05). Both cholesterol and DNA synthesis in circulating mononuclear cells from G6PD-deficient men were likewise reduced (p = 0.05). Conclusions: Since NADPH is a necessary cofactor for the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R), G6PD deficiency appears to be a naturally occurring model of HMG-CoA R restraint, whose consequences are similar to those produced on the same enzyme by statins. G6PD deficiency therefore results in protection against CVD, despite an increased susceptibility to oxidative stress.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingested by G6PD-deficient subjects (gene-nutrient interaction), or some oxidant drugs are assumed (gene-drug interactions), a life-threatening hemolysis can occur. However, the same defect results in lower cardiovascular disease (CVD) risk. Physiopathological, clinical and mortality studies of CVD risk in relation with G6PD deficiency have been surveyed. CVD risk in men was lowered in the G6PD-deficient state, and was associated with reduced levels of plasma low-density lipoprotein cholesterol (LDL-C) compared to the normal condition (p < 0.05). Both cholesterol and DNA synthesis in circulating mononuclear cells from G6PD-deficient men were likewise reduced (p = 0.05). Since NADPH is a necessary cofactor for the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R), G6PD deficiency appears to be a naturally occurring model of HMG-CoA R restraint, whose consequences are similar to those produced on the same enzyme by statins. G6PD deficiency therefore results in protection against CVD, despite an increased susceptibility to oxidative stress.
Author Muntoni, Sandro
Muntoni, Sergio
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CitedBy_id crossref_primary_10_1111_ene_15418
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Cites_doi 10.3109%2F07853890008998823
10.1161%2F01.ATV.0000205850.49390.3b
10.1161%2FCIRCULATIONAHA.104.499095
10.1016%2FS0140-6736%2894%2990566-5
10.1016%2FS0140-6736%2804%2915690-0
10.1128%2FMCB.25.12.5146-5157.2005
10.1016%2Fj.atherosclerosissup.2006.01.005
10.1126%2Fscience.1059344
10.1038%2F343425a0
10.1161%2F01.ATV.0000168411.72483.08
10.1161%2F01.ATV.0000122852.22604.78
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Issue 1-2
Keywords Wine consumption
Cholesterogenesis
3-Hydroxy-3-methylglutaryl coenzyme A reductase
Glucose-6-phosphate dehydrogenase
Favism
Cardiovascular diseases
Gene-nutrient interactions
Language English
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PublicationTitle Journal of nutrigenetics and nutrigenomics
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References Luzzatto L, Mehta A, Vulliamy T: Glucose 6-phosphate dehydrogenase deficiency; in Scriver CR, Beaudet AL, Sly WS (eds): The Metabolic Basis of Inherited Diseases, ed8.New York, McGraw Hill, 2001, pp 4517-4553.
Park J, Rho HK, Kim KH, Choe SS, Lee YS, Kim JB: Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. Mol Cell Biol 2005;25:5146-5157.1592363010.1128%2FMCB.25.12.5146-5157.2005
Hanukoglu I, Rapaport R: Routes and regulation of NADPH production in steroidogenic mitochondria. Endocr Res 1995;21:231-241.
Scandinavian Simvastatin Survival Study (4S): Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.796807310.1016%2FS0140-6736%2894%2990566-5
Park J, Choe SS, Choi AH, Kim KH, Yoon MJ, Suganami T, Ogawa Y, Kim JB: Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals. Diabetes 2006;55:2939-2949.
Barrett-Connor E, Khaw K-F, Yen SSC: A prospective study of dehydroepiandrosterone sulphate, mortality and cardiovascular disease. N Engl J Med 1986;315:1519-1524.
Leopold JA, Cap A, Scribner AW, Stanton RC, Loscalzo J: Glucose 6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability. FASEB J 2001;15:1771-1773.
Siperstein MD: Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth. J Lipid Res 1984;25:1462-1468.6397554
Luzzatto L: Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica 2006;91:1303-1306.
Muntoni S, Pintus F, Mascia P, Pintus P, Ganga E, Menotti A: Lipidi plasmatici nella condizione di carenza di glucosio-6-fosfato deidrogenasi. Giorn Arterioscl 1989;14:123-129.
Oluboyede OA, Esan GJF, Francis TI, Luzzatto L: Genetically determined deficiency of glucose 6-phosphate dehydrogenase (type A-) is expressed in the liver. J Lab Clin Med 1979;93:783-789.
Muntoni S: G-6-PD deficiency: a naturally-occurring model of HMG-CoA reductase restraint. Ann Nutr Metab 2003;47:229-254.
Lapchak PA, Chapman D, Nunez SY, Zivian JA: Dehydroepiandrosterone is neuroprotective in a reversible spinal cord ischemia model. Stroke 2003;31:1953-1957.
Istvan ES, Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160-1164.1134914810.1126%2Fscience.1059344
Beutler E: Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991;324:169-174.
Cocco P, Todde P, Fornera S, Manca MB, Manca P, Sias AR: Mortality in a cohort of men expressing the glucose 6-phosphate dehydrogenase deficiency. Blood 1998;91:706-709.9427729
Luzzatto L, Usanga EA, Reddy S: Glucose 6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science 1969;164:839-842.
Sanna E, Bruno R, Cosseddu GG, Floris G, Salis A, Silvetti M: Present-day G-6-PD deficit in Sardinia with respect to malarial morbidity and mortality in the past. Z Morph Anthrop 1990;78:257-267.
Leopold JA, Loscalzo J: Oxidative enzymophaties and vascular disease. Arterioscl Thromb Vasc Biol 2005;25:1332-1340.
Muntoni S, Muntoni Sa: Genetic influences on serum LDL levels and type 1 diabetes incidence in Sardinia; in Simopulos AP, Pavlou KN (eds): Nutrition and Fitness: Diet, Genes, Physical Activity and Health. Basel, Karger, 2001, vol 89, pp 76-82.
Ceriello A, Motz E: Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The Common Soil hypothesis revisited. Arterioscl Thromb Vasc Biol 2004;24:816-823.1497600210.1161%2F01.ATV.0000122852.22604.78
Marks PH, Banks J: Inhibition of mammalian glucose-6-phosphate dehydrogenase by steroids. Proc Natl Acad Sci USA 1960;46:447-452.
Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 1990;343:425-430.196782010.1038%2F343425a0
Evans JL, Goldfine ID, Maddux BA, Grodsky GM: Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 2003;52:1-8.
Long WK, Wilson SW, Frenkel EP: Association between red cell glucose 6-phosphate variants and vascular disease. Am J Hum Genet 1967;19:35-53.
Lopez SA, Wingo C, Hebert JA: Total serum cholesterol and urinary dehydroepiandrosterone in humans. Atherosclerosis 1976;24:471-481.
Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6 phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E-/- Mice. Arterioscler Thromb Vasc Biol 2006;26:910-916.1643970610.1161%2F01.ATV.0000205850.49390.3b
Heart Protection Study Collaborative Group: Effect of cholesterol lowering with simvastatin on stroke and other major cardiovascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767.1501648510.1016%2FS0140-6736%2804%2915690-0
Muntoni S, Pintus F, Mascia P, Pintus P, Podda E, Cabiddu GF, Tronci P, Ganga E, Contini PP, Congiu P, Trudu A, Baule GM, Sanna A, Onorato D, Mereu P, Seccareccia F, Conti S, Menotti A: The effects of wine consumption on plasma cholesterol levels are blunted in men deficient in glucose 6-phosphate dehydrogenase. Proc IX Int Symp DALM, Florence, 1986, abstr, p 150.
Zalba G, Beloqui O, San José G, Moreno MU, Fortuño A, Dìez J: NADPH oxidase-dependent superoxide production is associated with carotid intima-media thickness in subjects free of clinical atherosclerotic disease. Arterioscler Thromb Vasc Biol 2005;25:1452-1457.1586074410.1161%2F01.ATV.0000168411.72483.08
Endres M: Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006;7:31-35.1650342210.1016%2Fj.atherosclerosissup.2006.01.005
Blackburn H: The potential for prevention of atherosclerosis in children. Ann NY Acad Sci 1991;623:2-8.
Quesney-Huneeus V, Wiley MH, Siperstein MD: Isopentenyladenine as a mediator of mevalonate-regulated DNA replication. Proc Natl Acad Sci USA 1980;77:5842-5846.
Comparato C, Altana C, Bellosta S, Baetta R, Paoletti R, Corsini A: Clinically relevant pleiotropic effects of statins: drug properties on effect of profound cholesterol reduction? Nutr Metab Cardiovasc Dis 2001;11:328-343.
Loscalzo J: Oxidant stress: A key determinant of atherothrombosis. Biochem Soc Trans 2003;31:1059-1061.14505479
Muntoni Sa, Manca MR, Cocco PL, Meloni L, Muntoni S: Glucose 6-phosphate dehydrogenase deficiency and coronary heart disease (abstract). Nutr Metab Cardiovasc Dis 2004;14:299.
Battistuzzi G, D'Urso M, Toniolo D, Persico GM, Luzzatto L: Tissue-specific levels of human glucose 6-phosphate dehydrogenase correlate with methylation of specific sites at the 3′ end of the gene. Proc Natl Acad Sci USA 1985;82:1465-1469.
Matsui R, Xu S, Maitland KA, Hayes A, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6 phosphate dehydrogenase deficiency decreases the vascular response to angiotensin II. Circulation 2005;112:257-263.1599868410.1161%2FCIRCULATIONAHA.104.499095
Chan TK, Todd W, Wong CC: Tissue enzyme levels in erythrocyte glucose 6-phosphate dehydrogenase deficiency. J Lab Clin Med 1965;66:937-942.
Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A: Non-lipid-related effects of statins. Ann Med 2000;32:164-176.1082132310.3109%2F07853890008998823
ref8
ref7
ref9
ref4
ref3
ref6
ref11
ref5
ref10
ref2
ref1
References_xml – reference: Luzzatto L, Usanga EA, Reddy S: Glucose 6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science 1969;164:839-842.
– reference: Oluboyede OA, Esan GJF, Francis TI, Luzzatto L: Genetically determined deficiency of glucose 6-phosphate dehydrogenase (type A-) is expressed in the liver. J Lab Clin Med 1979;93:783-789.
– reference: Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6 phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E-/- Mice. Arterioscler Thromb Vasc Biol 2006;26:910-916.1643970610.1161%2F01.ATV.0000205850.49390.3b
– reference: Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 1990;343:425-430.196782010.1038%2F343425a0
– reference: Muntoni S, Pintus F, Mascia P, Pintus P, Ganga E, Menotti A: Lipidi plasmatici nella condizione di carenza di glucosio-6-fosfato deidrogenasi. Giorn Arterioscl 1989;14:123-129.
– reference: Beutler E: Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991;324:169-174.
– reference: Scandinavian Simvastatin Survival Study (4S): Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.796807310.1016%2FS0140-6736%2894%2990566-5
– reference: Evans JL, Goldfine ID, Maddux BA, Grodsky GM: Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 2003;52:1-8.
– reference: Luzzatto L: Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica 2006;91:1303-1306.
– reference: Ceriello A, Motz E: Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The Common Soil hypothesis revisited. Arterioscl Thromb Vasc Biol 2004;24:816-823.1497600210.1161%2F01.ATV.0000122852.22604.78
– reference: Heart Protection Study Collaborative Group: Effect of cholesterol lowering with simvastatin on stroke and other major cardiovascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767.1501648510.1016%2FS0140-6736%2804%2915690-0
– reference: Hanukoglu I, Rapaport R: Routes and regulation of NADPH production in steroidogenic mitochondria. Endocr Res 1995;21:231-241.
– reference: Istvan ES, Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160-1164.1134914810.1126%2Fscience.1059344
– reference: Long WK, Wilson SW, Frenkel EP: Association between red cell glucose 6-phosphate variants and vascular disease. Am J Hum Genet 1967;19:35-53.
– reference: Park J, Rho HK, Kim KH, Choe SS, Lee YS, Kim JB: Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. Mol Cell Biol 2005;25:5146-5157.1592363010.1128%2FMCB.25.12.5146-5157.2005
– reference: Marks PH, Banks J: Inhibition of mammalian glucose-6-phosphate dehydrogenase by steroids. Proc Natl Acad Sci USA 1960;46:447-452.
– reference: Chan TK, Todd W, Wong CC: Tissue enzyme levels in erythrocyte glucose 6-phosphate dehydrogenase deficiency. J Lab Clin Med 1965;66:937-942.
– reference: Siperstein MD: Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth. J Lipid Res 1984;25:1462-1468.6397554
– reference: Park J, Choe SS, Choi AH, Kim KH, Yoon MJ, Suganami T, Ogawa Y, Kim JB: Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals. Diabetes 2006;55:2939-2949.
– reference: Endres M: Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006;7:31-35.1650342210.1016%2Fj.atherosclerosissup.2006.01.005
– reference: Comparato C, Altana C, Bellosta S, Baetta R, Paoletti R, Corsini A: Clinically relevant pleiotropic effects of statins: drug properties on effect of profound cholesterol reduction? Nutr Metab Cardiovasc Dis 2001;11:328-343.
– reference: Muntoni S, Muntoni Sa: Genetic influences on serum LDL levels and type 1 diabetes incidence in Sardinia; in Simopulos AP, Pavlou KN (eds): Nutrition and Fitness: Diet, Genes, Physical Activity and Health. Basel, Karger, 2001, vol 89, pp 76-82.
– reference: Lopez SA, Wingo C, Hebert JA: Total serum cholesterol and urinary dehydroepiandrosterone in humans. Atherosclerosis 1976;24:471-481.
– reference: Barrett-Connor E, Khaw K-F, Yen SSC: A prospective study of dehydroepiandrosterone sulphate, mortality and cardiovascular disease. N Engl J Med 1986;315:1519-1524.
– reference: Leopold JA, Cap A, Scribner AW, Stanton RC, Loscalzo J: Glucose 6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability. FASEB J 2001;15:1771-1773.
– reference: Leopold JA, Loscalzo J: Oxidative enzymophaties and vascular disease. Arterioscl Thromb Vasc Biol 2005;25:1332-1340.
– reference: Quesney-Huneeus V, Wiley MH, Siperstein MD: Isopentenyladenine as a mediator of mevalonate-regulated DNA replication. Proc Natl Acad Sci USA 1980;77:5842-5846.
– reference: Luzzatto L, Mehta A, Vulliamy T: Glucose 6-phosphate dehydrogenase deficiency; in Scriver CR, Beaudet AL, Sly WS (eds): The Metabolic Basis of Inherited Diseases, ed8.New York, McGraw Hill, 2001, pp 4517-4553.
– reference: Blackburn H: The potential for prevention of atherosclerosis in children. Ann NY Acad Sci 1991;623:2-8.
– reference: Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A: Non-lipid-related effects of statins. Ann Med 2000;32:164-176.1082132310.3109%2F07853890008998823
– reference: Loscalzo J: Oxidant stress: A key determinant of atherothrombosis. Biochem Soc Trans 2003;31:1059-1061.14505479
– reference: Muntoni S: G-6-PD deficiency: a naturally-occurring model of HMG-CoA reductase restraint. Ann Nutr Metab 2003;47:229-254.
– reference: Sanna E, Bruno R, Cosseddu GG, Floris G, Salis A, Silvetti M: Present-day G-6-PD deficit in Sardinia with respect to malarial morbidity and mortality in the past. Z Morph Anthrop 1990;78:257-267.
– reference: Zalba G, Beloqui O, San José G, Moreno MU, Fortuño A, Dìez J: NADPH oxidase-dependent superoxide production is associated with carotid intima-media thickness in subjects free of clinical atherosclerotic disease. Arterioscler Thromb Vasc Biol 2005;25:1452-1457.1586074410.1161%2F01.ATV.0000168411.72483.08
– reference: Muntoni S, Pintus F, Mascia P, Pintus P, Podda E, Cabiddu GF, Tronci P, Ganga E, Contini PP, Congiu P, Trudu A, Baule GM, Sanna A, Onorato D, Mereu P, Seccareccia F, Conti S, Menotti A: The effects of wine consumption on plasma cholesterol levels are blunted in men deficient in glucose 6-phosphate dehydrogenase. Proc IX Int Symp DALM, Florence, 1986, abstr, p 150.
– reference: Battistuzzi G, D'Urso M, Toniolo D, Persico GM, Luzzatto L: Tissue-specific levels of human glucose 6-phosphate dehydrogenase correlate with methylation of specific sites at the 3′ end of the gene. Proc Natl Acad Sci USA 1985;82:1465-1469.
– reference: Muntoni Sa, Manca MR, Cocco PL, Meloni L, Muntoni S: Glucose 6-phosphate dehydrogenase deficiency and coronary heart disease (abstract). Nutr Metab Cardiovasc Dis 2004;14:299.
– reference: Lapchak PA, Chapman D, Nunez SY, Zivian JA: Dehydroepiandrosterone is neuroprotective in a reversible spinal cord ischemia model. Stroke 2003;31:1953-1957.
– reference: Matsui R, Xu S, Maitland KA, Hayes A, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6 phosphate dehydrogenase deficiency decreases the vascular response to angiotensin II. Circulation 2005;112:257-263.1599868410.1161%2FCIRCULATIONAHA.104.499095
– reference: Cocco P, Todde P, Fornera S, Manca MB, Manca P, Sias AR: Mortality in a cohort of men expressing the glucose 6-phosphate dehydrogenase deficiency. Blood 1998;91:706-709.9427729
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Snippet Background/Aims: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced...
The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through...
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StartPage 49
SubjectTerms Cardiovascular Diseases - epidemiology
Cardiovascular Diseases - genetics
Diet
Food
Genetic Predisposition to Disease
Glucosephosphate Dehydrogenase Deficiency - genetics
Humans
Mini Review
Oxidation-Reduction
Title Gene-Nutrient Interactions in G6PD-Deficient Subjects – Implications for Cardiovascular Disease Susceptibility
URI https://karger.com/doi/10.1159/000109874
https://www.ncbi.nlm.nih.gov/pubmed/19918114
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