**2. Vitamin C Transport**

Most mammals synthesize vitC in the liver by enzymatic conversion of glucose; however, a few species, including humans, guinea pigs and bats, lack a functional L-gulono-lactone oxidase enzyme catalyzing the final step in the biosynthesis and, therefore, rely completely on a dietary supply of vitC [32–34]. After consumption, vitC is absorbed from the intestinal lumen and released into the bloodstream. The dose-to-plasma concentration relationship is reflected in a saturation curve, attaining an initial steep and non-linear course, until steady-state is reached, defining plasma saturation at around 70 μM in humans [25]. At doses above saturation, urinary excretion is increased and oral bioavailability decreased, thereby sustaining steady-state equilibrium [25]. In the gastro-intestinal tract, the ionized form of vitC, ascorbate (ASC), and its oxidized counterpart, dehydroascorbic acid (DHA), are absorbed through different transporter systems with an increased affinity for ASC (*K*m of 0.2 mM) compared to DHA (*K*m 0.8 mM) and following a Michaelis-Menten absorption rate, where saturation reflects increases in substrate concentration [21,35]. The distribution from plasma to tissues is differentially regulated, and organs and tissues vary considerably in vitC content, as depicted in Figure 1. Within the body, the brain has a uniquely high vitC level [22,36] and is able to maintain a superior concentration relative to most other organs during periods of vitC deficiency [37–39], placing the brain as an organ of particular interest when assessing the effects of vitC deficiency.

The tight regulation of vitC homeostasis is primarily controlled by four regulatory systems: (i) intestinal uptake (bioavailability); (ii) tissue accumulation and distribution; (iii) rate of utilization and recycling; and (iv) renal excretion and reabsorption [26] (Figure 1). This is achieved by different mechanisms, including passive diffusion, facilitated diffusion, active transport and recycling [40].

**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.
