Vitamin C (Ascorbic Acid)

1. Introduction

Vitamin C, also known as L-ascorbic acid ($text{C}_6text{H}_8text{O}_6$), is a water-soluble vitamin and essential nutrient for humans. It is a simple carbohydrate derivative with a structure similar to glucose [1]. Unlike most mammals, humans lack the enzyme L-gulonolactone oxidase, which is necessary to synthesize vitamin C, and must therefore obtain it through diet or supplementation [2].

Chemical/Botanical Basics

Ascorbic acid is a potent reducing agent (electron donor), which is the basis for its key biological functions. It can be reversibly oxidized to its unstable form, dehydroascorbic acid (DHAA). Both forms are biologically active, but DHAA is quickly reduced back to ascorbic acid inside the cell [3].

Mechanism of Action

Vitamin C’s primary roles are as a powerful antioxidant and an essential enzyme cofactor [3].

• Antioxidant Role: As a primary water-soluble, non-enzymatic antioxidant in plasma and tissues, vitamin C neutralizes harmful free radicals and reactive oxygen species (ROS), protecting vital biomolecules such as proteins, lipids, carbohydrates, DNA, and RNA from oxidative damage [3]. It also regenerates other antioxidants, such as $alpha$-tocopherol (Vitamin E), from their oxidized forms [2].
• Cofactor Role: Vitamin C is a required cofactor for eight human enzymes, including three involved in collagen hydroxylation, two involved in carnitine biosynthesis, and three involved in neurotransmitter synthesis (e.g., norepinephrine) [3]. It functions by maintaining the enzyme-bound metal ions (like iron and copper) in their reduced state, which is necessary for the enzymes’ catalytic activity [3].

2. Chemical Composition/Key Bioactive Roles

The biological activity of Vitamin C is primarily due to its role as a cofactor in various enzymatic reactions.

Compound	Chemical Class	Key Bioactive Roles
L-Ascorbic Acid	Water-soluble vitamin, Antioxidant	Potent reducing agent, neutralizes ROS and free radicals [3]
Dopamine $beta$-monooxygenase	Monooxygenase Cofactor	Synthesis of the neurotransmitter norepinephrine [3]
Prolyl and Lysyl Hydroxylases	Dioxygenase Cofactor	Essential for the hydroxylation of collagen, crucial for connective tissue stability [2, 3]
Trimethyllysine and $gamma$-Butyrobetaine Hydroxylases	Dioxygenase Cofactor	Essential for the biosynthesis of L-carnitine, which transports fatty acids for energy production [3]
Peptidyl-glycine $alpha$-amidating monooxygenase	Monooxygenase Cofactor	Amidation of peptide hormones [3]
TET and Jumonji Demethylases	Dioxygenase Cofactor	Involved in epigenetic regulation (DNA and histone demethylation) [3]

3. Health Benefits

Cardiovascular Disease Prevention

Higher circulating levels of vitamin C are inversely associated with the risk of cardiovascular disease (CVD) [3]. Vitamin C contributes to cardiovascular health by protecting against endothelial dysfunction, which is an early step in the development of atherosclerosis. Supplementation has been shown to improve flow-mediated dilation (FMD), a marker of endothelial function, in subjects with existing CVD risk factors [3].

Common Cold

While prophylactic vitamin C supplementation does not significantly reduce the risk of developing a cold in the general population, it does appear to modestly reduce the duration of the cold by 8% in adults and 14% in children [4].

• High-Intensity Exercise: Prophylactic intake of 250 mg/day to 1 g/day of vitamin C has been shown to reduce the incidence of the common cold by 50% in individuals exposed to extreme physical exercise (e.g., marathon runners) or cold environments [4].
• Treatment: Taking vitamin C after the onset of cold symptoms does not appear to affect cold duration or symptom severity [4].

Iron Absorption

Vitamin C significantly enhances the absorption of nonheme iron (the form of iron found in plant-based foods) by reducing ferric iron ($text{Fe}^{3+}$) to the more readily absorbed ferrous iron ($text{Fe}^{2+}$) in the stomach [2].

4. Dosage and Usage

Recommended Dietary Allowance (RDA)

The RDA for vitamin C is set to maintain near-maximal neutrophil vitamin C concentration with minimal urinary excretion [3].

Life Stage	Age	Males (mg/day)	Females (mg/day)
Adults	19 years and older	90 mg	75 mg
Smokers	19 years and older	125 mg	110 mg
Pregnancy	19 years and older	–	85 mg
Lactation	19 years and older	–	120 mg
Children	9-13 years	45 mg	45 mg

Smokers require an additional 35 mg/day due to increased oxidative stress from cigarette smoke [3].

Food Sources

Excellent sources of vitamin C include citrus fruits, berries, tomatoes, potatoes, and green leafy vegetables [2].

5. Safety and Precautions

Vitamin C is generally considered safe when taken at recommended doses. The primary concern with high-dose supplementation is gastrointestinal upset [3].

Side Effects

The most common side effects from high oral doses (above 2,000 mg/day) are gastrointestinal disturbances such as diarrhea, nausea, and stomach cramps [3, 5].

Upper Limit (UL)

The tolerable Upper Intake Level (UL) for adults is 2,000 mg (2 g) per day. This limit is set to prevent osmotic diarrhea and other gastrointestinal disturbances [3].

Age Group	Upper Limit (UL) (mg/day)
Adults	2,000 mg
Adolescents (14-18 yrs)	1,800 mg
Children (9-13 yrs)	1,200 mg
Children (4-8 yrs)	650 mg

Contraindications and Warnings

• Kidney Stones: High-dose vitamin C supplementation (e.g., 2,000 mg/day or more) is a concern for individuals with a history of kidney stones or pre-existing renal disease, as vitamin C is metabolized to oxalate, which can contribute to stone formation [3, 5].
• Iron Overload: Because vitamin C enhances iron absorption, individuals with hereditary hemochromatosis (a condition of iron overload) should avoid high doses of vitamin C as it can exacerbate the condition [5].
• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: High doses of vitamin C in individuals with G6PD deficiency may cause hemolysis (the destruction of red blood cells) [5].

Drug Interactions

Vitamin C may interact with certain medications [5]:

• Chemotherapy and Radiation: Vitamin C’s antioxidant properties may interfere with the effectiveness of some chemotherapy and radiation therapies, which rely on generating ROS to kill cancer cells. Patients undergoing these treatments should consult their oncologist before taking high-dose vitamin C [5].
• Statins and Niacin: Some studies suggest that high-dose antioxidants, including vitamin C, may blunt the increase in high-density lipoprotein (HDL) cholesterol caused by a combination of statins and niacin, although this is not consistently supported by all research [5].
• Anticoagulants (Blood Thinners): High doses of vitamin C may theoretically interfere with the effectiveness of blood thinners like warfarin, though this interaction is not well-established [5].

6. References

[1] A comprehensive review and recent advances of vitamin C. Food Chem X. 2024;2:100251. Available from: https://www.sciencedirect.com/science/article/pii/S026387622400251X

[2] Abdullah M, Jamil RT, Attia FN. Vitamin C (Ascorbic Acid). StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 May 1. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499877/

[3] Vitamin C. Linus Pauling Institute Micronutrient Information Center. Oregon State University. Available from: https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

[4] Vitamin C – Health Professional Fact Sheet. Office of Dietary Supplements (ODS). National Institutes of Health (NIH). Available from: https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/

[5] Vitamin C. Mayo Clinic. Available from: https://www.mayoclinic.org/drugs-supplements-vitamin-c/art-20363932