Antioxidant Action of Vitamin-C
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Antioxidant Action of Vitamin-C

Oxidative stress/Hypoxia is induced by a wide range of environmental factors including UV stress, pathogen invasion (hypersensitive reaction), oxygen shortage, etc. Generation of ROS (Reactive Oxygen Species) is characteristic feature of such stress conditions. Of the ROS, both Hydrogen Peroxide and Superoxide are produced in a number of cellular reactions and by various enzymes such as Lipoxygenases, Peroxidases, NADPH Oxidase, Xanthine Oxidase, etc to name a few. Consequences of oxidative stress depend on tissue and/or species (i.e. their tolerance to Anoxia), on membrane properties, on endogenous antioxidant content and on the ability to induce the response in the antioxidant system (Ref.1). The formation of ROS is prevented by an antioxidant system that includes low molecular mass antioxidants such as, Vitamin-C (Ascorbate or Ascorbic Acid), Glutathione, Tocopherols; enzymes regenerating the reduced forms of antioxidants, and ROS-interacting enzymes such as SOD (Superoxide Dismutase), Peroxidases and Catalases (Ref.2 and 3). Ascorbic acid (Asc) is considered a powerful antioxidant, scavenging ROS and reactive nitrogen species. Although it is a hydrophilic molecule, it is involved in the protection of hydrophobic compounds such as membrane lipids, through a cooperative action with vitamin E. Asc acts regenerating alpha-tocopherol from alpha-tocopheryl radical. So, the antioxidant power of vitamin E is increased by the presence of vitamin C (Ref.4).

In human tissues apart from stress conditions, ROS is mostly generated during cytokine signal transduction pathways and signaling involving growth factors and Rho GTPases. Intracellular ROS signals are transduced to specific transcription factor signaling pathways by redox-sensitive signal transducers including the GTP binding proteins Ras and Rac; Ser/Thr and Tyr protein kinases including PKC (Protein Kinase-C), PKA (Protein Kinase-A); and MAPK (Mitogen-Activated Protein Kinase) members, which lead to the transcriptional activation of the jun and fos genes as well as the phosphorylation of the c-Jun and c-Fos proteins. c-Jun is activated by serine phosphorylation induced by JNK (c-Jun NH2-Terminal Kinase), and ATF2 (Activating Transcription Factor-2) is activated by p38 phosphorylation. The fos gene is activated by the transcription factor Elk1 (ETS-domain protein Elk1) binding to the fos promoter. Elk1, an Ets family transcription factor, is in turn activated by ERK(Extracellular Signal-Regulated Kinase) phosphorylation. NF-KappaB (Nuclear Factor-KappaB) is retained in the cytoplasm complexed by the inhibitor protein I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells). Activation of Cytokine Receptors generate ROS to activate IKKs (I-KappaB Kinases), which in turn leads to the phosphorylation and degradation of I-KappaB by the 26S Proteasome. The degradation of I-KappaB allows NF-KappaB (p50/p65 heterodimers) to translocate to the nucleus and bind to elements in gene promoters. The redox-regulated transcription factors function independently or act in concert to cooperatively activate transcription from oxidant-responsive genes but under extreme physiological conditions these show aberrant functions resulting in the onset of oncogenesis and/or autoimmune disorders (Ref.5 and 6). In a similar context oxidant stress mediates acute barrier dysfunctional responses and vascular disorders through several pathways; (i) ROS may activate Phospholipases or Ser/Thr and Tyr protein phosphatases {i.e., PLC (Phospholipase-C), PLD (Phospholipase-D), and PLA2 (Phospholipase-A2)}, which further generate a multitude of cellular messengers (Phosphoinositides and Ca2+ (Calcium)) and cofactors that activate Actin-binding proteins like MLC (Myosin Light Chain) and Fln (Filamin) leading to formation of stress fiber or the Actino-Myosin complex; (ii) ROS may modulate cellular messengers through direct and indirect oxidative modification of the signals themselves or their regulating cofactors, which in turn will affect the downstream targets, Actin-binding proteins and adhesion molecules; and (iii) ROS may alter the structure and function of structural proteins and adhesion molecules by direct oxidative modification. Additionally, ROS depletes cellular ATP, which has profound effects on the cell cytoskeleton. These acute responses to ROS are proposed mechanisms that lead to a decrease in cortical Actin band, increased stress fibers, and loss/disassembly of tight and adherens junctions (Ref.7).

Under such stress conditions Vitamin-C (an essential water-soluble Vitamin), acts as a primary antioxidant in plasma and within cells that quenches ROS and serves as a cofactor for enzymes involved in the synthesis of Collagen, neurotransmitters and Carnitine. This helps in the strengthening of tissues. Dietary Vitamin-C is essential for humans, primates, guinea pigs, and several other animals and insects that lack L-Gulono-Lactone Oxidase, the final enzyme in its biosynthetic pathway from Glucose. Under physiological conditions, Vitamin-C predominantly exists in its reduced form, Ascorbic Acid or Ascorbate; it also exists in trace quantities in the oxidized form, DHA (Dehydroascorbic Acid) (Ref.2). At physiological pH, Ascorbate occurs in the monoanion form. Loss of the first electron results in the formation of AFR (Ascorbate Free Radical). AFR is not very reactive and mild oxidants such as Fe3+(CN)6 (Ferricyanide) remove a second electron and convert the AFR to DHA and itself gets reduced to Fe2+(CN)6 (Ferrocyanide). The PMOR (Plasma Membrane Oxidoreductases), a multienzyme complex that includes NADPH- Ferricyanide Reductase and NADPH Oxidase along with Cytochrome-B5 Reductases play a vital role in the conversion of AFR to DHA. There are two known mechanisms for transporting Vitamin-C into the cells. A universal system, present in all cells, transports intracellular levels Vitamin-C as DHA via facilitative GLUTs (Glucose Transporters). Once inside the cell, DHA is rapidly reduced and accumulates as Vitamin-C, either directly by the action of Glutathione or in reactions catalyzed by TxnRd (Thioredoxin Reductase) or Glrx (Glutaredoxin). NADH-dependent mechanisms may also contribute to this mechanism. TxnRd and Glrx, also fall under the category of ROS-sensitive signal transducers. The second transport system is functional in cells where Vitamin-C is directly transported into cells via sodium-dependent Ascorbate co-transporters or SVCTs (Sodium-Dependent Vitamin-C Transporters) (Ref.8). The human SVCTs (Sodium-Dependent Vitamin-C Transporters) (Ref.6). The human GMCSF (Granulocyte-Macrophage Colony-Stimulating Factor) phosphorylates CSFRs (Granulocyte-Macrophage Colony-Stimulating Factor Receptors) and facilitates JAK2(Janus Kinase-2) activation for an enhanced uptake of DHA through GLUTs. This results in increased intracellular levels of Vitamin-C. GLUTs do not transport Ascorbate in vivo. Increased levels of Vitamin-C and DHA suppress the formation of ROS and activation of IKKs to induce the antioxidant defense and cooperation (and/or compensation) between different antioxidant systems are the determinants of the competence of the antioxidant system (Ref.9).

Such mechanisms substantiate the importance of ROS in cytokine and growth factors signaling and indicate a role for Vitamin-C in down modulating such signaling responses to counteract stress conditions within tissues. These actions point to Vitamin-C as a potent antioxidant and a regulator of redox-signal transduction in host defense cells and therefore has a possible role in controlling inflammatory responses (Ref.7).