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Bioactivity of Ascorbic Acid
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This entry is adapted from the peer-reviewed paper 10.3390/antiox11010153

Ascorbic acid (L-enantiomer) is commonly known as vitamin C composed of six carbons and related to the C6 sugars. It is the aldono-1,4-lactone of a hexonic acid with an enediol group on carbons 2 and 3. As an essential micronutrient, ascorbic acid plays a vital role in maintaining normal metabolic processes and homeostasis within the human body.

Ascorbic acid Bioactivity Antioxidant

1. Antioxidant

The by-products of normal cell metabolism are reactive oxygen species (ROS), including superoxide radicals (O2·−), singlet oxygen (1O2), hydrogen peroxide (H2O2) and highly reactive hydroxyl radicals (OH·). The adverse effect of ROS is that it can initiate a cascade of radicals, producing hydroxyl free radicals and other destructive species. These further induce protein and DNA damage, lipid peroxidation and finally lead to cell apoptosis [1]. The antioxidant defense system cannot fully eliminate the toxic ROS accumulated in the cells, that is, the so-called “oxidative stress” occurs [2]. In addition to enzymatic reactions, ROS can also be eliminated through non-enzymatic means such as antioxidants. Ascorbic acid is a free radical and other oxygen species scavenger, which can protect cells from oxidative damage caused by ROS. Antiradical capability commonly reflects the antioxidant ability, and ascorbic acid in foodstuff and bio-systems acts as antioxidant. As the most effective and natural antioxidant with the least side effects, ascorbic acid can inhibit various diseases caused by oxidative stress in the body, such as cancer, cardiovascular disease, aging and cataracts [3]. The mortality from these diseases is inversely related to plasma concentration of ascorbic acid [4]. Ascorbic acid and its derivatives can reduce the level of lipid peroxidation in vivo due to aging [5]. In the absence of transition metals, ascorbic acid can reduce the frequency of mutations induced by H2O2 in human cells [6]. Compared with other polyphenols or flavonoid antioxidants, ascorbic acid terminates the free radical chain reaction through disproportionation reaction, and the reaction products such as DHA and 2,3-diketogulonic acid are non-damaging and non-radical products [7]. Another manifestation of antioxidant property is that ascorbic acid can form relatively stable ascorbic acid free radicals to donate single electrons [8]. As reported, antioxidants can also repair tryptophan free radicals produced by the one-electron oxidation of free tryptophan in lysozyme to maintain protein integrity [9].
Ascorbic acid is also used as an antioxidant to protect the sensory and nutritional properties of foods. As an anti-browning agent, it can inhibit the browning of vegetables and fruits caused by oxidation. The formation of quinones mediated by polyphenol oxidase causes the accumulation of H2O2, which in turn causes the browning of polyphenols mediated by peroxidase [10]. Ascorbic acid inhibits browning by reducing the o-quinone produced by polyphenol oxidase to the original diphenol through a process called “deactivation reaction” [11]. In addition to the regeneration mechanism of polyphenols, the protective effect is also attributed to the competitive inhibition of polyphenol oxidase activity by ascorbic acid. Meanwhile, addition of ascorbic acid causes a decrease in pH and is not conducive to the expression of polyphenol oxidase activity [12]. In meat products, ascorbic acid is widely used as a natural agent for color retention, which can inhibit lipid oxidation and maintain color stability [13]. Compared with other organic acids such as malic acid, citric acid and tartaric acid, ascorbic acid had the best protective effect on the quality of cured meat and was a suitable ingredient for cured meat products [14]. The surface of the pork sprayed with ascorbic acid and a mix of that and rosemary extract maintained good stability in color, water content and pH after frozen storage [15]. It is worth noting that this dietary source of ascorbic acid added in meat products is often overlooked. Norwegian researchers found that the content of ascorbic acid in sausages is 11–40 mg/mL, but ascorbic acid is usually ignored in the table of food ingredients because the added ascorbic acid is used as a color retention agent rather than a nutrient component. As a result, the actual ascorbic acid intake of Norwegian residents increased by 3–10% [16]. The ascorbic acid added to the edible polysaccharide film can eliminate or quench the free radicals generated by radiation. As a radiation inhibitor, ascorbic acid can inhibit the decrease in the viscosity of carrageenan caused by radiation and protect its rheological properties [17]. Ascorbic acid can inhibit food-borne pathogens in the early stage of biofilm formation due to its anti-quorum sensing activity and inhibition of extracellular polymer production. The efficacy of ascorbic acid is related to its concentration and the strain. For Escherichia coli and Staphylococcus aureus, the inhibitory effect of ascorbic acid at 25 mg/mL is the greatest, and lower concentrations of ascorbic acid are ineffective. For Listeria monocytogenes, ascorbic acid at 0.25 mg/mL shows an inhibitory effect [18].

2. Pro-Oxidant

Pro-oxidant activity is defined as the ability of antioxidants to reduce transition metal ions to a lower oxidation state, which refers to the Fenton reaction [19]. In the Fenton reaction, transition metal ions such as Fe3+ are reduced by ascorbic acid and then Fe2+ further react with oxygen and hydrogen peroxide to form highly active and destructive hydroxyl radicals [20]. Ascorbic acid does not always express antioxidant activity, and may be converted into a pro-oxidant and show toxic effects under certain conditions. The effect of ascorbic acid on the redox properties of bovine hemoglobin is dual with an antioxidant effect at the initial stage of the reaction. During the reaction process, ascorbic acid generates hydrogen peroxide under the mediation of oxygen or oxygenated hemoglobin. With the consumption of ascorbic acid, its own scavenging ability cannot balance the accumulated hydrogen peroxide, which leads to the formation of bilirubin and accelerates the oxidation of hemoglobin [21]. Ascorbic acid may transform from an antioxidant under physiological conditions to a pro-oxidant at higher concentrations. Researchers found that supplementation of 500 mg of ascorbic acid in the diet for 6 weeks increases the level of oxidative damage to peripheral blood lymphocytes, although this result is still controversial in the academic community [22][23]. Furthermore, the presence of transition metal ions in the system is also a key factor for ascorbic acid exerting pro-oxidant activity [24]. In mayonnaise, the added ascorbic acid works as a lipid antioxidant or pro-oxidant depending on the presence or absence of the fat-soluble antioxidant vitamin E. In the system containing vitamin E, the synergistically antioxidant effect of these two vitamins is stronger than the pro-oxidant effect of ascorbic acid. Without the addition of vitamin E, the hydrogen peroxide at the interface of the oil droplets promotes the lipid oxidation of lipoprotein particles in the mayonnaise, which in turn induces the oxidation of apolipoproteins and produces volatile odors [25]. In addition, dehydroascorbic acid may irreversibly degrade and produce highly reactive carbonyl intermediates, which can induce glycosylation of proteins. This is a non-enzymatic, non-specific reaction between carbonyl and amino groups, which is involved in a variety of age-related diseases [26]. It is worth noting that the pro-oxidation of ascorbic acid can induce the apoptosis of cancer cells, thereby exerting anti-cancer effects to a certain extent. As reported, the copper-dependent cellular redox state is an important factor in the cytotoxic effect of ascorbic acid on cancer cells. Ascorbic acid mobilizes nuclear copper to cause pro-oxidative cleavage of cellular DNA, and nuclear copper serves as a new molecular target for the toxic effects of cancer cells [27][28]. From this perspective, the pro-oxidation effect of ascorbic acid is beneficial.

3. Co-Factors

Ascorbic acid can also be used as a co-factor for enzymes and other bioactive components to indirectly exert biological activities by acting as a free radical scavenger and electron transfer donor/acceptor to directly express its antioxidant properties. In the metabolic process of animals and plants, ascorbic acid does not directly participate in the catalytic cycle. As an enzyme co-factor, ascorbic acid exerts its indispensable function by regulating hydroxylation processes in multiple enzymatic reactions. For the active part of the enzyme with iron or copper, the role of ascorbic acid is to maintain the transition metal ions of these enzymes in a reduced form to exert their maximum physiological activity [29]. Ascorbic acid is a co-factor for non-heme iron α-ketoglutarate-dependent dioxygenases such as prolyl 4-hydroxylase with the role in the synthesis of collagen. As an electron donor, ascorbic acid can keep iron in the ferrous state, thereby maintaining the full activity of collagen hydroxylase. This promotes the hydroxylation of proline and lysine residues, allowing pro-collagen correct intracellular folding [30]. Ascorbic acid can also promote catecholamine synthesis by circulating tetrahydrobiopterin and enhance adrenal steroid production by increasing the expression of tyrosine hydroxylase [31]. As a co-factor, it helps dopamine β-hydroxylase convert dopamine to norepinephrine [32]. In addition, ascorbic acid can regulate cardiomyopathy and neurometabolic diseases. For example, as a co-factor for carnitine synthesis, it can shuttle fatty acids into the mitochondria and reduce oxidative stress [33]. In some clinical situations, as a co-factor for the biosynthesis of amidated opioid peptides, taking ascorbic acid can exhibit analgesic effects [34].

4. Synergistic Effect

As a natural antioxidant, ascorbic acid mostly exists in the form of coexistence with other components in nature. Combining it with other antioxidants may produce additive or even synergistic effects. Ascorbic acid and vitamin E, as chain-scission antioxidants, have an important inhibitory effect on the auto-oxidation of cell membrane polyunsaturated liposomes in vivo and the oxidation of lipids in vitro [35]. Studies have shown that the combination of 15% ascorbic acid and 1% α-tocopherol can significantly inhibit erythema and the formation of sunburn cells [36]. The synergy between α-tocopherol and ascorbic acid relies on the ability of ascorbic acid to regenerate α-tocopherol, and maintain the antioxidant capacity of α-tocopherol through circulation and inhibition of pro-oxidation [37]. The combined use of ascorbic acid and gallic acid is a promising strategy to prevent the formation of advanced glycation end products, showing the synergistic effect in the inhibition of amyloid cross-β-structure and protein carbonyl formation in fructose-induced BSA glycosylation samples [38]. Lycopene can inhibit inflammation and further stimulate the release of anti-inflammatory cytokine IL-10 when it combined with ascorbic acid and/or α-tocopherol [39]. Understanding the synergy between ascorbic acid and other bioactive compounds allows the antioxidant system of foods and drugs to be selected more specifically.

References

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