Vitamin A

1. Introduction – What is the product, chemical/botanical basics, mechanism of action

Vitamin A is a group of fat-soluble retinoids, primarily retinol and retinyl esters, that are essential for human health [1]. It is obtained from the diet in two main forms: preformed vitamin A (retinol and retinyl esters), found in animal products like dairy, eggs, and liver, and provitamin A carotenoids (such as beta-carotene, alpha-carotene, and beta-cryptoxanthin), found in plant-based foods [1, 2].

The body converts provitamin A carotenoids into retinol in the intestine. Retinol is then converted into its biologically active forms: retinal and retinoic acid [1].

Mechanism of Action

Vitamin A is critical for several fundamental biological processes:

• Vision: Retinal is an essential component of rhodopsin, the light-sensitive protein in the retina that is crucial for low-light vision [1].
• Gene Regulation and Cellular Differentiation: Retinoic acid binds to nuclear receptors, regulating gene transcription. This mechanism controls cell growth and differentiation, playing a vital role in the normal formation and maintenance of the heart, lungs, eyes, and other organs [1].
• Immune Function: Vitamin A supports immune function by regulating the differentiation and function of immune cells [1].

2. Chemical Composition/Key Bioactive Roles

The term “Vitamin A” encompasses several compounds, collectively known as retinoids, and their precursors, the provitamin A carotenoids.

Compound	Classification	Primary Bioactive Role
Retinol	Preformed Vitamin A	Transport and storage form; converted to retinal and retinoic acid.
Retinyl Esters	Preformed Vitamin A	Storage form of Vitamin A, primarily in the liver.
Retinal (Retinaldehyde)	Active Retinoid	Essential component of rhodopsin for vision.
Retinoic Acid	Active Retinoid	Regulates gene expression, cell differentiation, growth, and immune function.
Beta-Carotene	Provitamin A Carotenoid	The most efficiently converted precursor to Vitamin A; also acts as an antioxidant.
Alpha-Carotene	Provitamin A Carotenoid	Precursor to Vitamin A; contributes to Vitamin A status.
Beta-Cryptoxanthin	Provitamin A Carotenoid	Precursor to Vitamin A; contributes to Vitamin A status.

3. Health Benefits – Detailed health benefits with scientific evidence

Vitamin A and carotenoids have been studied for their roles in several health outcomes:

Vision and Age-Related Macular Degeneration (AMD)

Vitamin A is fundamental to vision. Studies have investigated the use of supplements to prevent or slow the progression of AMD, a leading cause of vision loss in older people.

• AREDS Trial: The Age-Related Eye Disease Study (AREDS) found that a high-dose combination supplement, including beta-carotene (15 mg or 25,000 IU), vitamin C, vitamin E, and zinc, reduced the risk of developing advanced AMD by about 25% over 5 years in people with intermediate or advanced AMD in one eye [1, 3].
• AREDS2 Trial: The follow-up AREDS2 trial confirmed the benefit of the supplement formulation. It also found that replacing beta-carotene with lutein (10 mg) and zeaxanthin (2 mg) provided the same protective effect against advanced AMD, and the lutein/zeaxanthin combination was associated with a 26% lower risk of advanced AMD in participants with the lowest dietary intake of these carotenoids [1, 4].

Cancer

The relationship between vitamin A/carotenoid supplementation and cancer risk is complex and has yielded mixed results, including significant warnings.

• ATBC and CARET Trials: Two large randomized clinical trials, the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study and the Carotene and Retinol Efficacy Trial (CARET), showed that high-dose beta-carotene supplementation increased the risk of lung cancer in current and former smokers.
  • The ATBC trial found that 20 mg/day of beta-carotene increased the risk of lung cancer and mortality in male smokers [1, 5].
  • The CARET trial found that a combination of 30 mg/day of beta-carotene plus 7,500 $mu$g RAE (25,000 IU)/day retinyl palmitate increased the risk of lung cancer and death from lung cancer in current and former smokers and men occupationally exposed to asbestos [1, 6].
• Non-Smokers: The increased risk of lung cancer was not observed in non-smokers, and other observational studies have not found an association between high intakes of vitamin A from food and cancer risk [1].

Measles

Vitamin A supplementation has been shown to reduce the risk of morbidity and mortality from measles in children with vitamin A deficiency, which is common in low-income countries.

• A 2022 Cochrane Review found that vitamin A supplementation reduced the risk of measles-related death by 50% in children [1]. Doses are typically high, ranging from 15,000 $mu$g RAE (50,000 IU) to 60,000 $mu$g RAE (200,000 IU), administered as a single dose or every 4 to 6 months [1].

4. Dosage and Usage – Recommended dosages, food sources if applicable

Recommended Dietary Allowances (RDAs)

The RDA for Vitamin A is expressed in Retinol Activity Equivalents ($mu$g RAE) to account for the different bioactivities of retinol and provitamin A carotenoids.

Age Group	Male ($mu$g RAE/day)	Female ($mu$g RAE/day)
19–50 years	900 $mu$g RAE	700 $mu$g RAE
51+ years	900 $mu$g RAE	700 $mu$g RAE
Pregnancy	–	770 $mu$g RAE
Lactation	–	1,300 $mu$g RAE

Conversion Factors:

• 1 $mu$g RAE is equivalent to:
  • 1 $mu$g retinol
  • 2 $mu$g supplemental beta-carotene
  • 12 $mu$g dietary beta-carotene
  • 24 $mu$g dietary alpha-carotene or beta-cryptoxanthin [1]

Food Sources

Preformed vitamin A is highest in liver, fish, and dairy products. Provitamin A carotenoids are abundant in leafy green, orange, and yellow vegetables and fruits.

Food Source	Vitamin A Content ($mu$g RAE per serving)
Beef liver, pan fried, 3 ounces	6,582
Sweet potato, baked in skin, 1 whole	1,403
Spinach, frozen, boiled, ½ cup	573
Carrots, raw, ½ cup	459
Cantaloupe, raw, ½ cup	135

5. Safety and Precautions – Side effects, contraindications, drug interactions, warnings

Safety Warnings (Tolerable Upper Intake Levels – UL)

The Tolerable Upper Intake Level (UL) is the maximum daily intake unlikely to cause adverse health effects. The UL applies to preformed vitamin A (retinol and retinyl esters) from food and supplements, but not to provitamin A carotenoids [1].

Age Group	UL for Preformed Vitamin A ($mu$g/day)
19+ years	3,000 $mu$g
Pregnancy	3,000 $mu$g
Lactation	3,000 $mu$g

Side Effects and Toxicity

• Acute Toxicity (Hypervitaminosis A): Ingestion of a very high dose (typically more than 100 times the RDA) can cause severe headache, blurred vision, nausea, dizziness, muscle aches, and coordination problems. In severe cases, it can increase cerebral spinal fluid pressure, leading to drowsiness, coma, and even death [1].
• Chronic Toxicity: Regular consumption of high doses can cause dry skin, painful muscles and joints, fatigue, depression, and abnormal liver test results [1].
• Carotenodermia: Long-term, excessive intake of beta-carotene can cause the skin to turn yellow-orange, a harmless condition that is reversible upon discontinuing intake [1].

Serious Safety Warning for Smokers and Pregnant Women

• Smokers: High-dose supplementation with beta-carotene (20-30 mg/day), with or without retinyl palmitate, has been shown to significantly increase the risk of lung cancer and all-cause mortality in current and former smokers [1, 5, 6].
• Pregnancy (Teratogenicity): Total intakes of preformed vitamin A that exceed the UL (3,000 $mu$g RAE or 10,000 IU daily) can cause congenital birth defects (teratogenic effects), including malformations of the eye, skull, lungs, and heart. Women who are or might be pregnant are advised not to take high-dose vitamin A supplements [1].

Drug Interactions

Vitamin A has the potential to interact with certain medications [1]:

• Retinoids (e.g., Acitretin, Isotretinoin, Bexarotene): These are synthetic derivatives of vitamin A used to treat severe acne, psoriasis, and some cancers. Taking vitamin A supplements in combination with these drugs can significantly increase the risk of hypervitaminosis A [1].
• Orlistat (Alli, Xenical): This weight-loss drug can decrease the absorption of fat-soluble vitamins, including vitamin A and beta-carotene, potentially leading to low plasma levels [1].
• Tetracyclines: Taking high doses of vitamin A with tetracycline antibiotics may increase the risk of a condition called pseudotumor cerebri (increased pressure in the brain) [7].

6. References

[1] Office of Dietary Supplements (ODS). Vitamin A and Carotenoids – Health Professional Fact Sheet. National Institutes of Health (NIH). Available at: https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/[2] Blaner WS, Vitamin A and Provitamin A Carotenoids. In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition. 11th ed. Cambridge, Massachusetts: Wiley-Blackwell; 2020:73-91.[3] Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417-36. Available at: https://pubmed.ncbi.nlm.nih.gov/11594942/[4] Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013 May 15;309(19):2005-15. Available at: https://pubmed.ncbi.nlm.nih.gov/23648932/[5] The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994 Apr 14;330(15):1029-35. Available at: https://pubmed.ncbi.nlm.nih.gov/8127329/[6] Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens PA Jr, Valanis B, Williams JH Jr, Barnhart S, Cherniack G, Brodkin K, Hammar S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1150-5. Available at: https://pubmed.ncbi.nlm.nih.gov/8602180/[7] Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014:260-77. (Cited for general information on drug interactions, specifically tetracyclines).