Why Vitamin C Could Be an Excellent Complementary Remedy to Conventional Therapies for Breast Cancer

2. Chemistry and Biochemistry of Vitamin C

Ascorbic acid is a water-soluble carbohydrate similar to glucose. However, unlike glucose, it contains the highly reactive “ene-diol” group. This group transforms a relatively inactive sugar to a powerful reducing agent in aqueous solution, which readily donates one or two electrons to radicals and oxidants, generating the relatively stable monodehydroascorbate (MDHA) radical, and the fully oxidized dehydroascorbic acid (DHA). Both DHA and MDHA can be reversibly reduced to ascorbate, as shown in Figure 1 [7,8].

DHA is transported inside the cell by sodium vitamin C transporters 1 and 2 (SVCT1 and SVTC2, respectively) [9]. Inside the cell, DHA can be degraded to 2,3-diketogulonate, oxalate, and L-threonate that can be discarded by the kidney [10].

Oxidation of ascorbate by free radicals or reactive oxygen species (ROS) can be performed inside or outside the cell. Therefore, the antioxidant action of ascorbate can decrease the concentration of ROS [11]. On the other hand, when injected intravenously, ascorbate can reach millimolar concentrations, which lead to its action as a pro oxidant [12]. The pro oxidant activity is due to an association with metal ions such as Fe3+ and Cu2+ that can be chelated by ascorbate [13]. In the presence of oxygen-reduced iron, ions react with hydrogen peroxide (H2O2) to develop reactive hydroxyl radicals (HO) or peroxide ions (O2•−) by stimulating the reaction of Fenton (Figure 1) and Haber–Weiss chemistry [14,15].

Vitamin C is an crucial cofactor for many iron- and copper-containing enzymes due to its ability to maintain these transition metals in the reduced state in which the activity of these enzymes is optimized [16].

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Vitamin C-dependent enzymes are classified into two groups: copper-containing monooxygenases and iron-containing and α-ketoglutarate-dependent dioxygenases (αKGDDs). αKGDDs uses oxygen and α-ketoglutarate as co-substrates while producing CO2 and succinate. Among the reactions catalyzed by αKGDDs are a wide range of hydroxylation reactions such as those involved in collagen synthesis, carnitine synthesis, noradrenaline synthesis, demethylation of protein, DNA and RNA, and hypoxia-inducible factor lα (HIF1α) stability. Thus, vitamin C regulates a variety of fundamental biological processes [13].

In nearly all mammals, ascorbic acid is synthesized in the kidney or liver using glucose from the blood by a number of reactions, as shown in Figure 2. Each reaction, with exclusion of the last one, is regulated by a specific enzyme. In the last reaction, the 2-keto-L-gulonolactone after being synthesized is transformed into ascorbic acid.

In humans, mutations dating from millions of years ago have destroyed the ability to synthesize L-gulonolactone oxidase, which is an enzyme necessary to transform L-gulonolactone into 2-keto-L-gulonolactone [12]. This is a clear example of a genetic disease that has previously been considered an avitaminosis.

Since humans are unable to synthesize vitamin C, this is required as an essential dietary supplement [17]. The recommended supplementary dose for an adult is about 100 mg per day in order to generate a 50 micromolar concentration of vitamin C in the plasma. Nonetheless, the concentration of vitamin C is different in different tissues. Circulating leucocytes, pituitary gland, adrenal glands, liver, brain, and skeletal muscle accumulate higher levels of vitamin C than plasma [18]. An elevated concentration of vitamin C in cells seems to indicate the need of ascorbate as a cofactor or to decrease the levels of ROS [19].

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