VITAMIN A

Vitamin A (Retinol)

Vitamin A is a fat-soluble vitamin essential for life, of both animal and plant origin. Unlike water-soluble vitamins, they are stored in the body, especially in the liver and fatty tissue. Therefore, it may have toxic effects when taken in excess.

Vitamin A can be obtained from the diet in the form of products of animal origin (retinol and close derivatives) or provitamin A (carotenoids) obtained from vegetables. The term vitamin A is often associated with retinol. Although retinol is actually the predominant form of retinoids in the human body, the main biologically active molecules are oxidized 11-cis-retinal and all-trans-retinoid acid derivatives (ATRA).

 

Herbal Sources

Carotenoids are yellow to orange organic pigments found in a variety of fruits and vegetables. Some of the best-known carotenoids are β-carotene, α-carotene, lutein, lycopene, and cryptoxanthin. β-carotene is the most abundant in the diet. While the main contributors to β-carotene intake are carrots, spinach, and tomato products, β-cryptoxanthin is most commonly obtained from various citrus fruits and citrus juices. β-Cryptoxanthin and other carotenoids are found in plants both free and esterified with fatty acids (lauric, myristic, palmitic). Rich sources of cryptoxanthin or esters, in addition to the previously mentioned citrus fruits (satsuma tangerines, tangerines, clementines, mineolas, and oranges), include persimmons, cayenne peppers and capsicums, papayas, sea buckthorn, loquats, mangoes, and apricots. The highest carotenoid content is found in fully ripe fruits.

 

Animal Sources

A major source of human intake of vitamin A is the preformed version of the vitamin found in foods of animal origin. Milk and dairy products, meat, eggs and fish are important sources.

 

Absorption

Vitamin A is obtained orally mainly from the diet. However, when used as a medicine, additional routes of administration are possible, including both intramuscular and topical routes. Retinyl esters found in foods of animal origin are almost completely absorbed, while the absorption of carotenoids is significantly lower.

 

Metabolism

Since most animal-based vitamin A takes the form of retinyl esters, these esters reach the intestine. Since micelle formation supports the absorption of fat-soluble compounds such as vitamin A in the small intestine, absorption increases when consumed with fatty meals. In addition to fat, some micronutrients such as zinc are also needed for the absorption of the vitamin. Once inside the enterocyte, retinol binds to a specific protein called cellular retinol binding protein (CRBP), which is responsible for the intracellular transport of retinol.

Carotenoids in intestinal cells can be metabolized to biologically active forms of vitamin A or excreted in their unchanged forms. Mostly β-carotene can be metabolized in the intestinal epithelium. Retinal, formed from β-carotene, is further oxidized to ATRA or reduced to retinol. When carotene intake is high, there is only a small conversion rate and most of the carotene is stored in adipose tissue and other fat reserves.

Absorbed or formed retinol is metabolized to retinyl esters, mostly palmitate, in enterocytes and secreted into the lymphatic system within chylomicrons. Chylomicrons containing retinyl esters formed in enterocytes eventually reach the bloodstream, where they can reach target tissues, especially the liver, the main storage organ of vitamin A in the body.

Once in the liver, some of the retinyl esters are hydrolyzed to retinol, and in this form they combine with RBP, a highly abundant protein that is synthesized in hepatocytes but is also found in some other tissues, such as adipose tissue. Once the retinol-RBP complex enters the bloodstream, it combines with another liver protein, transthyretin (TTR). TTR, whose name derives from the words "transports thyroxine and retinol", is better known for its thyroid hormone transport function, but it also plays a role in the kinetics of vitamin A. In fact, TTR can bind to RBP before its secretion into the circulatory system, forming a stable complex necessary for the correct delivery of retinol to target cells and preventing the degradation of RBP in the kidneys. The retinol-RBP complex is taken up by target cells via plasmalemmal transporters, which play a key role in the recognition of retinol blood carriers and the cellular uptake of retinol. Not all retinol in hepatocytes is secreted by RBP. Part of the retinol is transported to the stellate cells of the liver, where it is metabolized to retinyl esters and forms the main reservoir of vitamin A in the body.

Generally, vitamin A is stored in the form of retinyl esters. Fat tissue and other organs can also store retinoids. When needed, these storage organs release retinoids into the blood. Circulating retinoids generally bind to blood proteins, especially albumin and RBP. These complexes can be taken up by target cells, for example, through lipoprotein receptors or by stimulation by the retinoic acid 6 receptor (STRA6). Retinol found in target cells is mainly used in the creation of ATRA. In this pathway, retinol is first metabolized to retinal by alcohol dehydrogenases and then binds to CRBP. In the second step, retinal dehydrogenases oxidize retinal to ATRA, which then binds to cellular retinoic acid binding protein (CRABP). ATRA, the acidic form of vitamin A, is the end product of vitamin A oxidation and cannot be reduced back to retinal or retinol and stored.

 

Elimination

Elimination of retinoids occurs via the kidneys or via the liver into the bile. Since stored retinoids formed in the body are stored in different organs, their excretion from the body is slower than water-soluble vitamins. After stopping intake, months may pass before any vitamin A deficiency is noticed.

 

Factors Affecting Vitamin A Pharmacokinetics

• Drugs and (patho)physiological conditions can directly affect the absorption of the vitamin.

• Drugs such as estrogens and oral contraceptives have been reported to increase plasma concentrations of RBP, thereby increasing retinoid blood levels.

• Alcohol consumption is an important factor mediating the inhibition of vitamin A metabolism. Retinol concentrations are significantly reduced in alcoholic liver disease.

 

Pharmacokinetics of Vitamin A in Pregnancy

During pregnancy, the concentration of retinol in plasma decreases in the first trimester and gradually increases again, reaching normal values ​​before birth. Transfer of RBP from mother to fetus occurs only in the first trimester. The fetus can then synthesize its own RBP. It has been reported that high maternal vitamin A intake may lead to teratogenic effects on the developing fetus.

 

Vitamin A Functions

Seeing

The active vitamin A derivative is 11-cis-retinal. It is associated with the protein opsin, a G-coupled protein receptor in the retina. The complex is known as rhodopsin, a pigment important for light perception. Retinol deficiency leads to impaired vision in low light due to insufficient rhodopsin formation. This condition causes night blindness, also called nyctalopia. Low-light vision may improve after plasma retinol levels return to normal. However, it takes several weeks to fully regain normal function.

 

Gene Expression

Vitamin A is an important factor in gene regulation. This effect is exerted through interaction with nuclear receptors (NRs). NRs are ligand-activated transcription factors that can modulate target gene expression through direct interaction with DNA upon ligand binding. Retinoids are known to interact with a diverse family of nuclear receptors. The first receptor identified was named retinoic acid receptor α (RARa) due to its ability to bind retinoic acid (ATRA) with high affinity. RARs are generally involved in cell signaling. The second receptor family with high affinity for retinoids is RXR. This receptor represents the key to the functioning of RAR and many other nuclear receptors. Because its presence is necessary for the formation of heterodimers and subsequently the transcriptional machinery. Another family of receptors that interact with retinoids are peroxisome proliferative activated receptors (PPARs). Highly specific ligands for these receptors are fatty acids and play a role in energy homeostasis, fatty acid metabolism and inflammation.

 

Immunity

The adaptive immune system is another process in which vitamin A plays an important role. The vitamin acts as a cofactor in the proliferation and differentiation of regulatory T cells and various immune functions through indirect processes. IL-2 levels increase in the presence of vitamin A, which stimulates the differentiation of T cells into regulatory T cells, which are important mediators in the prevention of autoimmune responses.

 

Wound healing and epidermal regeneration

In injured tissues, retinoids promote epidermal regeneration and normal tissue restoration. ATRA mediates these functions by promoting collagen and fibronectin synthesis and proliferation of keratinocytes, promoting rapid restoration of a normal epidermis.

 

Embryogenesis

Embryogenesis is another process in which the presence of retinoid is crucial for proper growth and development.

 

Cancer

Several studies have shown that taking vitamin A supplements will help prevent or treat cancer. There is some evidence that it may actually be harmful. Taking beta-carotene or vitamin A supplements has been associated with a higher risk of lung cancer in people who smoke or drink alcohol. However, some researchers say more studies are needed to confirm this.

 

Lipid Metabolism

It plays a role in lipid metabolism and insulin sensitivity. Activation of RAR and PPAR regulates genes directly involved in glucose transport, fatty acid oxidation, lipolysis, and adipocyte differentiation.

 

Vitamin A Deficiency

• The most characteristic consequence of vitamin A deficiency is visual impairment. Early visual impairment is especially evident in low light situations.

• Epithelial changes due to vitamin A deficiency directly affect many systems in the human body and cause weight loss.

• Changes occur in the bronchorespiratory epithelium in the respiratory system and the tissue becomes more prone to infections.

• The skin may keratinize and the epidermis dries with subsequent appearance of papular eruptions and keratinization of sweat glands.

• Epithelial changes also occur in the urogenital system. At the level of the reproductive system, spermatogenesis is impaired and degeneration of the testicles may occur.

• In the gastrointestinal system, there is a decrease in the number of goblet cells in the intestines, epithelial change and pancreatic ductal epithelium metaplasia.

• Nerve lesions have also been reported.

• Taste and smell functions are also partially mediated by vitamin A through the synthesis of mucopolysaccharide, which is responsible for the sense of taste, and keratinization of this tissue leads to loss of sensation.

• In addition to a higher frequency of airway infections due to disrupted epithelium, general susceptibility to infection and inflammation are other symptoms of vitamin A deficiency.

• In addition to low vitamin A content, decreased levels of blood transport proteins are also found in malnourished children, further impairing vitamin A pharmacokinetics and subsequent functionality.

• Vitamin A is also known to interfere with iron metabolism. Its deficiency has a direct effect on iron levels through impairment of metabolism and heme synthesis. This is especially important in children and pregnant women. Therefore, vitamin A deficiency can cause anemia.

• Vitamin A has an important role in carcinogenesis.

 

VITAMIN A

Vitamin A (all-trans-retinol) is essential for mammalian vision, reproduction, immune functions, and cell differentiation. Vitamin A is found in animal and plant-derived forms. These are the retinol group of animal origin and the carotenes of plant origin. The most common form of vitamin A of animal origin is retinol which is stored in the body and converted into an active form for later use. This form of vitamin A is found in animal foods such as liver, eggs, fatty fish, milk and cheese. The most common form of carotene, which is the plant form of vitamin A, and the form that converts to retinol at the highest rate is beta-carotene. This form is found in yellow and orange coloured foods such as apricots and carrots.

 

Vitamin A and BCMO1 Gene Relationship

Carotenoids, such as β-carotene, obtained from plant foods are natural precursors of vitamin A in the human diet. β-carotene must be absorbed in the intestine before it can be metabolically converted to vitamin A. The conversion of β-carotene to retinoids is catalyzed by the enzyme β-carotene-15,15′-monoxygenase (BCMO1) in the enterocytes of the small intestine (Lobo, G. P. et al., 2013). Genetic variants in the BMCO1 gene cause the enzyme to be produced in varying amounts and affect the amount of vitamin A produced from dietary β-carotene. For this reason, it is recommended that people with variants in the BMCO1 gene also take vitamin A from animal sources in their diet.

The table above contains the genes and their polymorphisms involved in the metabolism of vitamin A. Homozygous rs11645428 G allele carriers are associated with a 51% reduction in transformation efficiency compared to homozygous A allele carriers. Similarly, carriers of the homozygous A allele of rs6420424 show a 59% lower transformation efficiency compared to carriers of the homozygous G allele. SNPs within the BCMO1 coding region (R267S; rs12934922 and A379V; rs7501331) revealed reduced catalytic activity (Lietz, G. et al., 2011). The BMCO1 rs6564851 variant is the best described allele in the literature and shows higher β-carotene and α-carotene concentrations in G allele carriers resulting from reduced conversion efficiency of the BMCO1 enzyme (Graßmann, S. et al., 2020).

Individuals who may have low vitamin A levels as a result of genetically reduced BCMO1 activity or who are “non-converters” should also maintain adequate dietary intake of iron, zinc, niacin, and riboflavin, which are essential for BCMO1 activity, to support vitamin A concentrations and potentially improve health outcomes (Glenn P.Lobo. et al., 2013; Perry JR. et al., 2009).

 

Therapeutic Use of Vitamin A

Different retinoids are used in various treatments. Besides well-known indications in hypovitaminosis and skin diseases, retinoids are also successfully used in cancer treatment. Although most retinoids are generally available in oral preparations, acitretin is indicated for topical use.

• In addition to malnutrition, retinol supplementation is indicated in the treatment of measles, where vitamin A requirements are significantly increased.

• Long-term substitution therapy with retinol is indicated in cases where retinol storage or distribution may be affected (steatorrhea, biliary obstruction, cirrhosis, gastrectomy).

• Supplementation therapy may also be indicated in other cases where retinol loss is observed, such as prolonged healing of injuries.

• The FDA has approved ATRA to treat various types of cancer, such as some lymphoma and leukemia, as well as cystic acne. Other retinoids used in cancer treatment are bexarotene and alitretinoin. It is common for tumors to develop resistance to ATRA treatment. Bexarotene can selectively bind to RXR and modulate gene expression and cell proliferation, and has been successfully used in the treatment of cutaneous T-cell lymphoma. Alitretinoin has been used in Kaposi's sarcoma where other treatments have failed. The major disadvantage of these synthetic derivatives is the multiple adverse effects they share with other retinoids, and this problem may be further accentuated with bexarotene.

• ATRA has multiple functions in the body and can be used therapeutically for different purposes depending on the method of administration. As a topical agent, it can be applied to treat acne and photoaging. Additionally, the anti-inflammatory effect of ATRA may also contribute to these effects.

• Retinoids are often used for skin disorders such as psoriasis, photodamage, seborrhea, acne, and ichthyosis. ATRA, isotretinoin, adapalene and acitretin are usually indicated for these purposes. However, several precautions should be taken into account for patients treated with them: avoiding sun exposure, using other topical treatments in the same area, delaying pregnancy, etc. In acne, isotretinoin is often recommended for its effectiveness and effect as a topical bactericide.

• Acitretin is an effective agent in psoriasis even as monotherapy. It is also used to treat discoid lupus due to its anti-inflammatory and antiproliferative effects. However, like other retinoids, it may cause side effects.

• Other expanded uses of retinoids are in the cosmetic industry and as dietary supplements. Many skin creams often contain retinyl palmitate, which can be absorbed and metabolized to retinol and then ATRA. Carotenoids are also widely used in cosmetic preparations due to their skin moisturizing properties. Carotenoids also have well-known UV protective effects in humans. This activity is directly linked to its antioxidative properties.

 

Supplement

Vitamin A supplements are available as retinol or retinyl palmitate. Tablets or capsules are available in various doses. The tolerable upper limit or safe upper limit is 10,000 IU. For any dose close to this amount, your doctor should help you determine the amount you should take. Most multivitamins contain the recommended dietary allowance (RDA) for vitamin A.

 

How to Buy?

Since vitamin A is absorbed along with fat in the diet, it is taken with food.

Daily dietary intakes for vitamin A:

Pediatric

• Babies from birth to 6 months: 400 mcg

• Babies 7 to 12 months: 500 mcg

• Children 1 to 3 years: 300 mcg

• Children ages 4 to 8: 400 mcg

• Children ages 9 to 13: 600 mcg

• Boys ages 14 to 18: 900 mcg

• Girls 14 to 18 years old: 700 mcg

Adult

• Men aged 19 and over: 900 mcg

• Women 19 years and older: 700 mcg

• Pregnant women ages 14 to 18: 750 mcg

• Pregnant women aged 19 and over: 770 mcg

• Breastfeeding women ages 14 to 18: 1,200 mcg

• Breastfeeding women aged 19 and over: 1,300 mcg

Too much vitamin A is toxic and can cause liver failure or even death. Symptoms of vitamin A toxicity include:

• Headache

• Burnout

• Muscle and joint pains

• Dry skin and lips

• Dry or irritated

• Nausea or diarrhea

• Hair loss

People with liver disease or diabetes should not take vitamin A supplements without a doctor's supervision.

Smokers and people who consume excessive amounts of alcohol should not take beta-carotene supplements.

Both vitamin A and beta-carotene can increase triglycerides, which are fats in the blood. They may even increase the risk of death from heart disease, especially in smokers.

If you are taking high doses of vitamin A, you may want to avoid eating carob. It increases the amount of vitamin A in your body.

Tetracycline antibiotics: People who take a type of antibiotic called tetracyclines and who also take high doses of vitamin A may be at risk for a condition called intracranial hypertension, which is an increase in brain fluid pressure. Tetracyclines include:

• Demeclocycline (Declomycin)

• Minocycline (Minosine)

• Tetracycline (Acromycin)

Antacids: One study suggests that a combination of vitamin A and antacids may be more effective at healing ulcers than antacids alone.

Anticoagulants (blood thinners): Long-term use or high doses of vitamin A may increase the risk of bleeding in people taking blood-thinning medications, especially warfarin (Coumadin).

Cholesterol-lowering medications (bile acid sequestrants): The medications cholestyramine (Questram) and colestipol (Colestid) may decrease your ability to absorb vitamin A, leading to lower levels in your body. A water-soluble form of vitamin A may be helpful. Another class of cholesterol-lowering drugs called statins can raise levels of vitamin A in your blood.

Doxorubicin: Doxorubicin is a medication used to treat cancer. Test-tube studies suggest that vitamin A may potentiate the effect of doxorubicin. If you are being treated for cancer, you should consult your oncologist before taking vitamin A or any supplement.

Drugs processed by the liver: Taking high doses of vitamin A along with some other drugs processed by the liver can cause liver damage or even liver failure. Some examples of drugs processed by the liver include acetaminophen (Tylenol), carbamazepine (Tegretol), isoniazid, and methotrexate.

Neomycin (Mycifradin): This antibiotic can decrease the body's ability to absorb vitamin A, especially when taken in large doses.

Omeprazole (Prilosec): Used for gastroesophageal reflux disease or heartburn, omeprazole may interact with beta-carotene supplements.

Retinoids: These medications are a synthetic form of vitamin A and are sometimes prescribed in high doses. People taking retinoids should not take additional vitamin A supplements. These drugs can also cause serious birth defects. Women of childbearing age must have two negative pregnancy tests and two types of birth control before taking these medications. Anyone taking retinoids will be monitored closely by their doctor. Retinoids include:

• Acitretin (Soriatan)

• Bexarotene (Targretin)

• Isotretinoin (Accutane)

• Tazarotene (Average)

Tretinoin (Retin-A): It is often prescribed as a skin cream to treat acne or reduce wrinkles and is not as concentrated as other retinoids. However, you may still want to avoid taking vitamin A supplements while using Retin-A.

Orlistat (Alli) and Olestra: Orlistat, a drug used for weight loss, and olestra, a substance added to some foods, block the body's absorption of fat and calories. They may also prevent the body from absorbing enough vitamin A. The Food and Drug Administration (FDA) recommends that food products containing olestra contain vitamin A and other fat-soluble vitamins.

 

 

 

REFERENCES

Graßmann S, Pivovarova-Ramich O, Henze A, Raila J, Ampem Amoako Y, King Nyamekye R, Bedu-Addo G, Mockenhaupt FP, Schulze MB, Danquah I. SNP rs6564851 in the BCO1 Gene Is Associated with Varying Provitamin a Plasma Concentrations but Not with Retinol Concentrations among Adolescents from Rural Ghana. Nutrients. 2020 Jun 16;12(6):1786. doi: 10.3390/nu12061786. PMID: 32560166; PMCID: PMC7353293. https://pubmed.ncbi.nlm.nih.gov/32560166/ 

Lietz G, Oxley A, Leung W, Hesketh J. Single nucleotide polymorphisms upstream from the β-carotene 15,15'-monoxygenase gene influence provitamin A conversion efficiency in female volunteers. J Nutr. 2012 Jan;142(1):161S-5S. doi: 10.3945/jn.111.140756. Epub 2011 Nov 23. PMID: 22113863. https://pubmed.ncbi.nlm.nih.gov/22113863/ 

Lobo GP, Amengual J, Baus D, Shivdasani RA, Taylor D, von Lintig J. Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX. J Biol Chem. 2013 Mar 29;288(13):9017-27. doi: 10.1074/jbc.M112.444240. Epub 2013 Feb 7. PMID: 23393141; PMCID: PMC3610974. https://pubmed.ncbi.nlm.nih.gov/23393141/ 

Perry JR, Ferrucci L, Bandinelli S, Guralnik J, Semba RD, Rice N, Melzer D; DIAGRAM Consortium, Saxena R, Scott LJ, McCarthy MI, Hattersley AT, Zeggini E, Weedon MN, Frayling TM. Circulating beta-carotene levels and type 2 diabetes-cause or effect? Diabetologia. 2009 Oct;52(10):2117-21. doi: 10.1007/s00125-009-1475-8. Epub 2009 Aug 7. PMID: 19662379; PMCID: PMC2746424. https://link.springer.com/article/10.1007/s00125-009-1475-8