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

Abstract

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.

High Doses of Vitamin C and Leukemia: In Vitro Update

“…Given the results obtained, it is reasonable to conclude that the Vitamin C added to the culture medium (in the form of sodium ascorbate) is rapidly internalized by the leukemic cells, and its "toxic" effects last for hours (days), even when the nutrient has been removed from the culture medium. This is in agreement with the notion that both normal and leukemic white blood cells tend to concentrate Vitamin C [70][71][72][73] to levels that are 10-100 fold higher than plasma [74,75], and it is in contrast with the view that hydrogen peroxide forms outside the tumor cells [31,32]. Neutrophils, in particular, accumulate Vitamin C via the sodium-dependent Vitamin C cotransporter 2 (SVCT2) [76], and have intracellular levels of 1-2 mM [77].…”

New Reference Values for Vitamin C Intake

“…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. Some limited data exist on the influence of genetic changes in manganese superoxide dismutase (SOD 2 ) and glucose transport proteins (SLC 2 ) on ascorbate levels in humans [28] .…”

“…Present data on the effect of genotype on plasma ascorbate concentration are insufficient to determine the requirements for vitamin C according to genotype variants [26,28] . Data from studies on the association between vitamin C intake or plasma ascorbate concentrations, respectively, and endpoints as the concentration of blood lipids, blood pressure, risk, severity and duration of common colds and the occurrence of chronic diseases are also no suitable criteria for deriving the requirement for vitamin C [26] (see 'Reference Values for Vitamin C Intake').…”

The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity

“…Notably, Vc is unstable in aqueous solution and spontaneously oxidizes to its biologically inactive form, dehydroascorbate (DHA) (1), also producing ascorbate radical as an intermediate product. Cells can take up DHA using a different type of low-affinity transporters: the glucose transporters GLUT1, GLUT2, GLUT3, GLUT4, GLUT8, and GLUT10 (3,4). Among these GLUT isoforms, only GLUT1 has a ubiquitous distribution (5,6).…”