2.2.2. Transporter Troubles

Based on the evidence presented above, animals unable to synthesize vitamin C appear to display an active transport system in the intestine that is both sensitive to varying levels of ascorbic acid and sodium-dependent. This implicates a role of the sodium-dependent vitamin C transport (SVCT) proteins. SVCT1 has been implicated in dietary ascorbate absorption in human enterocytes, as it is found primarily on the luminal side of intestinal cells and involved in trans-epithelial ascorbate transport [73–75]. However, mice genetically modified to remove functional expression of the SVCT1 gene (Slc23a1−/−) show similar intestinal ascorbate absorption as wild type mice [76], suggesting SVCT1 is not involved in this process in these animals. Indeed, the concentration of ascorbic acid needed in the drinking water of GULO knockout mice to maintain tissue saturation (3.3g/L or 18.75 mM) far exceeds the transport capacity of SVCT1, which has a measured *K*m below 250 μM [77]. On the other hand, the ability of rats to absorb dehydroascorbic acid has been linked to the intestinal expression of glucose transport proteins (GLUTs), namely GLUT2 and GLUT8 that show Km values of approximately 2–3 mM [63].


Unfortunately, little is known about differences in expression or regulation of the SVCTs between humans, guinea pigs, rats, and mice. Comparison of the amino acid sequences of mouse, rat, and human SVCT1 shows that seven amino acid residues are missing from the human SVCT1 sequence [90]. This deletion creates a potential protein kinase C (PKC)-binding site in the human sequence not found in rats or mice. Stimulation of PKC has been implicated in membrane trafficking of human SVCT1 [91]. Additionally, the *C*-terminal sequence of rat and mouse SVCT1 has a one-amino acid change in a critical four-amino acid sequence required for apical targeting of the transport protein [92]. SVCT2, responsible for uptake of ascorbate from the blood stream, contains an additional 56 amino acids in the *N*-terminal region of the human protein sequence that are not found in rats and mice [90]. The only study to date on a species difference in SVCT regulation found that buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, reduced the expression of both SVCT1 and SVCT2 in rat liver cell lines, a phenomenon not observed in human hepatoma cells [93].

Although the absorption of dehydroascorbic acid is not considered a major pathway for the maintenance of whole body ascorbic acid levels, it is considered an important scavenger pathway to maintain cellular ascorbate levels if extracellular ascorbate is oxidized to dehydroascorbic acid [94]. Since human erythrocytes do not express SVCT proteins [95], ascorbic acid transport across the plasma membrane is facilitated by dehydroascorbic acid uptake mediated through GLUTs.

Recent evidence suggests that GLUT1 is responsible for dehydroascorbic acid uptake in human red blood cells, enhanced by the co-expression of a protein called stomatin during erythropoiesis [78]. By contrast, mice lose GLUT1 during maturation, and GLUT4 is the predominant glucose transporter expressed in adult mouse erythrocytes [96]. GLUT4, by contrast, has diminished capacity to transport dehydroascorbic acid [97], which is reflected in the transport capacity of murine erythrocytes [78]. Interestingly, GLUT1 expression and the associated dehydroascorbic acid transport in red blood cells are found only in species unable to synthesize ascorbate—lacking from every animal with endogenous ascorbate-synthesis capacity, even in closely related species such as chinchilla and guinea pigs, or lemurs and margot monkeys [78]. Furthermore, this remarkable switch in glucose transport proteins may be indicative of differences in global gene expression patterns between ascorbate synthesizing *versus* non-synthesizing animals.
