Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331
Annual Review of Nutrition (Impact Factor: 8.36). 04/2013; 33(1). DOI: 10.1146/annurev-nutr-071812-161246
Source: PubMed


New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk. Expected final online publication date for the Annual Review of Nutrition Volume 33 is July 17, 2013. Please see for revised estimates.

33 Reads
    • "Most mammals are capable of de novo hepatic synthesis of Asc from glucose, through a biosynthetic pathway that employs the enzyme L-gulono-γ-lactone oxidase (GULO) for the terminal oxidation reaction [14] [15] [16] [17]. However, higher primates (including humans), guinea pigs, and some bats are obligatorily dependent on dietary sources of the vitamin [18] [19]. This requirement is due to an inactivation of the GULO gene [14] [15] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ascorbate is a co-factor in numerous metabolic reactions. Humans cannot synthesize ascorbate due to inactivation of the gene encoding the enzyme, l-gulono-γ-lactone oxidase, which is essential for ascorbate synthesis. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut, ascorbate within mammalian systems can regulate cellular iron uptake and metabolism. Ascorbate modulates iron metabolism by stimulating ferritin synthesis, inhibiting lysosomal ferritin degradation and decreasing cellular iron efflux. Furthermore, ascorbate cycling across the plasma membrane is responsible for ascorbate-stimulated iron uptake from low molecular-weight iron-citrate complexes, which are prominent in the plasma of individuals with iron-overload disorders. Importantly, this iron-uptake pathway is of particular relevance to astrocyte brain iron metabolism and tissue iron-loading in disorders such as hereditary hemochromatosis and β-thalassemia. Recent evidence also indicates that ascorbate is a novel modulator of the classical transferrin-iron uptake pathway, which provides almost all iron for cellular demands and erythropoiesis under physiological conditions. Ascorbate acts to stimulate transferrin-dependent iron uptake by an intracellular reductive mechanism, strongly suggesting that it may act to stimulate iron mobilization from the endosome. The ability of ascorbate to regulate transferrin iron uptake could help explain the metabolic defect that contributes to ascorbate-deficiency-induced anemia.
    No preview · Article · Jul 2014 · Free Radical Biology and Medicine
  • Source
    • "Therefore, it can be anticipated that this population is at greater risk of developing serum ascorbic acid deficiency if consumption of dietary vitamin C is inadequate. The specific nature of the molecules participating within the glutathione–vitamin C antioxidant cycle that play a role in protecting cells from oxidative damage are still an unresolved matter (Michels et al., 2013). However, the findings obtained hitherto indicate that some metabolic redundancy exists on the functions of glutathione and vitamin C. Cumulatively, the data suggests that functional GST enzymes exert a protective capacity against vitamin C deficiency when dietary vitamin C is insufficient (Cahill et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Advances in molecular biology, emergence of novel techniques and huge amount of information generated in the post-Human Genome Project era have fostered the emergence of new disciplines in the field of nutritional research: Nutrigenomics deals with the effect of diet on gene expression whereas nutrigenetics refers to the impact of inherited traits on the response to a specific dietary pattern, functional food or supplement. Understanding the role of micronutrient supplementation with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on individualized nutritional treatment and may provide the strategies for the development of safer and more effective dietary interventions. This overview of the various aspects of supplementation of micronutrients in the era of nutrigenetics and nutrigenomics may provide a better understanding of novel nutritional research approach and provide an additional insight that can be applied to the daily dietary practice.
    Full-text · Article · Mar 2014 · International Journal of Food Sciences and Nutrition
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Large cross-sectional population studies confirm that vitamin C deficiency is common in humans, affecting 5%-10% of adults in the industrialized world. Moreover, significant associations between poor vitamin C status and increased morbidity and mortality have consistently been observed. However, the absorption, distribution and elimination kinetics of vitamin C in vivo are highly complex, due to dose-dependent non-linearity, and the specific regulatory mechanisms are not fully understood. Particularly, little is known about how adaptive mechanisms during states of deficiency affect the overall regulation of vitamin C transport in the body. This review discusses mechanisms of vitamin C transport and potential means of regulation with special emphasis on capacity and functional properties, such as differences in the Km of vitamin C transporters in different target tissues, in some instances demonstrating a tissue-specific distribution.
    Full-text · Article · Aug 2013 · Nutrients
Show more