Abstract
Ascorbic acid (AA; or vitamin C) is an important physiological antioxidant and radical scavenger. Some mammalian species, including homo sapiens, have lost the ability to synthetize AA and depend on its nutritional uptake. Erythrocytes from AA-auxotroph mammals express high amounts of the glucose transporter GLUT1. This isoform enables rapid uptake of glucose as well as dehydroascorbate (DHA), the fully oxidized form of AA. Here, we explored the effects of DHA uptake on the redox metabolism of human erythrocytes. DHA uptake enhanced plasma membrane electron transport (PMET) activity. This process is mediated by DCytb, a membrane bound cytochrome catalyzing extracellular reduction of Fe3+ and ascorbate free radical (AFR), the first oxidized form of AA. DHA uptake also decreased cellular radical oxygen species (ROS) levels. Both effects were massively enhanced in the presence of physiological glucose concentrations. Reduction of DHA to AA largely depleted intracellular glutathione (GSH) and induced the efflux of its oxidized form, GSSG. GSSG efflux could be inhibited by MK-571 (IC50 = 5 μM), indicating involvement of multidrug resistance associated protein (MRP1/4). DHA-dependent GSH depletion and GSSG efflux were completely rescued in the presence of 5 mM glucose and, partially, by 2-deoxy-glucose (2-DG), respectively. These findings indicate that human erythrocytes are physiologically adapted to recycle AA both intracellularly via GLUT1-mediated DHA uptake and reduction and extracellularly via DCytb-mediated AFR reduction. We discuss the possibility that this improved erythrocyte-mediated AA recycling was a prerequisite for the emergence of AA auxotrophy which independently occurred at least twice during mammalian evolution.
Highlights
Ascorbic acid (AA), commonly known as vitamin C, is an antioxidant and radical scavenger
In this study we show that uptake of DHA largely affects the redox metabolism of human erythrocytes
In the light of pertinent phylogenetic findings, these results suggest that erythrocytes of the vitamin C auxotroph species homo sapiens are evolutionary adapted to maximize dietary uptake of vitamin C and minimize its loss in the blood stream
Summary
Ascorbic acid (AA), commonly known as vitamin C, is an antioxidant and radical scavenger. Rats with defects in AA biosynthesis require higher nutritional AA uptake than the “natural” AA auxotroph guinea pigs to prevent adverse systemic effects (Horio et al, 1985). This indicates that adaptations must have occurred during the evolution of AA auxotroph organisms to minimize systemic loss of vitamin C. Rapid recycling of DHA into the reduced AA state is crucial for vitamin C auxotrophs to minimize systemic loss of this vitamin This is likely to be an essential evolutionary adaptation to reduce irreversible degradation of DHA resulting from oxidative processes within the blood stream
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