Regulation of vitamin C homeostasis during deficiency

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 K(m) of vitamin C transporters in different target tissues, in some instances demonstrating a tissue-specific distribution.

Figure 1

Distribution of vitamin C in the body. Vitamin C is ingested, absorbed from the intestinal lumen and transported to various peripheral organs with the blood. Finally, vitamin C is excreted in the renal glomeruli and reabsorbed through the tubular systems. Tissue concentrations are dependent on all of these processes.

Figure 2

Transport mechanisms between intestines, blood and kidney. Ingested vitC is absorbed across the intestinal epithelium primarily by membrane transporters in the apical brush border membrane, either as ascorbate by sodium-coupled active transport via the sodium-dependent vitamin C transporter (SVCT) 1 transporter or as dehydroascorbic acid (DHA) through facilitated diffusion via glucose transporter (GLUT) 2 or GLUT3 transporters. Once inside the cell, DHA is efficiently converted to ascorbate (ASC) or transported to the blood-stream by GLUT1 and GLUT2 in the basolateral membrane, thereby maintaining a low intracellular concentration and facilitating further DHA uptake. ASC is conveyed to plasma by diffusion, possibly also by facilitated diffusion through volume-sensitive anion channels. SVCT2 located in the basolateral membrane enables re-uptake of ASC from plasma to the intestinal epithelium. In the kidney, ASC is excreted by glomerular filtration to the renal tubule lumen. Reabsorption is primarily achieved by SVCT1 transporters in the apical membrane, although diffusion from the luminal surface may also contribute to the overall uptake. While not confirmed in vivo, DHA is presumably re-absorbed in the renal tubule cells; however, the availability of DHA for re-absorption is thought to be negligible, due to the very low DHA concentrations in plasma. As in the intestinal epithelium, ASC can be released to the blood-stream through both passive and facilitated diffusion. GLUT2 transporters are located in the basolateral membrane, enabling transport of DHA to plasma.