The ultimate guide to Retinol: History, sources, benefits and commercial uses

Table of Contents




Retinol or Vitamin A1 is arguably the most indispensable vitamin for the human body, as it is required at all points of life, from embryogenesis to adulthood.1, 2 It is the alcohol (-OH) form of  Vitamin A that belongs to the family of fat-soluble vitamins.3 It was the first vitamin discovered. 

Animals, including human beings, cannot synthesize it de novo, therefore retinol must be obtained through foods and supplements.4 However, unlike most other vitamins, the body can store its various forms in considerable amounts; thus, minimizing the needs of its obligatory routine consumption in the diet.5 Retinols are obtained in the form of retinyl esters from foods of animal origin, like liver, meat, dairy products, etc.4 The vegetarian diet only provides a provitamin form i.e. carotenoids especially β-carotene which is later converted into retinol in the body.6 

Retinol supplements are clinically used to treat several health disorders related to vitamin deficiency, like night blindness, xerophthalmia, etc.7,8 Where its deficiency causes a variety of medical issues, its over-intake is also problematic as it can lead to bone problems, dry skin, liver enlargement, hypervitaminosis A, etc.9, 10, 11  Studies have also demonstrated that high intake during pregnancy is teratogenic i.e. causes birth defects in babies.12 


History – the course of Discovery, Isolation, and Synthesis of Retinol 

The incremental exploring course of vitamin A and retinoids is extended over a period of 130 years in history, but no single occasion can be regarded alone as the “discovery of Vitamin A”.13 In 1816 while conducting experiments on dogs, a physiologist, named François Magendie, found out that nutritional deprivation was causing corneal ulcerations and high mortality just like the clinical observations recorded among malnourished children in Paris.13 

In 1906, Frederick Gowland Hopkins, based on his experimental findings, hypothesized that there were some ‘so far unknown dietetic factors’ vital for maintaining a healthy life.13, 14 Later, in 1911, Wilhelm Stepp also supported this assumption and claimed that this active ingredient in milk was fat-like (lipoid) but was not fat itself. Following year (1912), Hopkins demonstrated that growth in rats required unknown accessory factors present in milk, other than carbohydrates, fats, and proteins.14

In 1913, a biochemist, Elmer McCollum, and his colleague Marguerite Davis at the University of Wisconsin–Madison identified this fat-soluble substance in butterfat and cod liver oil, just like  Thomas Burr Osborne and Lafayette Mendel who discovered it in butterfat, later in the same year at Yale.13  

Finally, in 1931, retinol was first isolated, and its chemical structure was elucidated by a Swiss chemist Paul Karrer.13, 15 In 1947, two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens synthesized retinol (Vitamin A1) for the first time in vitro.15 

Structural and Molecular Formula 

Retinol is a 20 carbon-containing hydrocarbon molecule as can be seen in its molecular formula i.e. (C20H30O) It possesses a β-ionone ring and a polyunsaturated side chain. A single hydroxyl group is attached at its one end. It chemically belongs to the family of isoprenoids (a group of compounds synthesized from isoprene units).16 The side chain is made up of two isoprenoid units, having a series of conjugated double bonds which are arranged in either cis or trans configuration. The 2D and 3D structural formula of retinol is shown in the figure. 


Chemical and Physical Properties of Retinol

The chemical and physical properties of retinol have been found either through experimentations, or automatic computation from the given chemical structure. Thus, these properties can be generally classified into two categories, i.e. experimental and computed properties, respectively.

Experimental properties

  • Physical Appearance: It appears as a yellow crystal or orange solid.17
  • Boiling Point: Retinol boils at around 279-280 °F (137-138 °C) at 10−6 mm Hg.17
  • Melting Point: The melting point of retinol is 144–147 °F (62–64 °C).18
  • Solubility: It is practically insoluble in water and glycerol; but soluble in solvents like absolute alcohol, methanol, ethanol, chloroform, acetone, ether, fats, oils, and benzene.17, 19
  • LogP: The Logarithm of Partial Coefficient (LogP) of retinol is 5.68.20
  • Shelf Life/Stability: Free retinol is sensitive to air-oxidation but its oil solution is very stable. It is not easily destroyed by heat. It is more stable in alkaline solution as compared to acidic ones. Ultraviolet (UV) radiations cause the inactivation of retinol.19
  • Refractive Index: Its index of refraction is 1.6410 at 20 °C/D.19
  • Fluorescence: On irradiation with strong Ultraviolet light, retinol solution gives a yellow-green fluorescence. 19
  • Distillation Point: At 5 x10-3 mm of Hg, it distills at 120-125 °C.
  • Isomers of retinol: Retinol has a variety of geometrical isomers due to the potential cis or trans arrangement of side chains around the four out of five double bonds in the polyene chain. The synthetic retinol exists in all-trans isomeric form. The geometric isomers of retinol are readily inter-converted in the body.
  • Vapor Pressure: At 25 °C, its vapor pressure is 7.5 X 10-8 mm of Hg.

Computed Properties 19


Molecular Weight286.5 g/mol
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count1
Rotatable Bond Count5
Monoisotopic Mass286.229666 g/mol
Exact Mass286.229666 g/mol
Topological Polar Surface Area20.2 ²
Heavy Atom Count21
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count4
Undefined Bond Stereocenter Count0
Covalently-Bonded Unit Count1
Compound Is Canonicalized


Synthesis of Retinol in Body

The de novo synthesis of retinol (Vitamin A1) does not occur in animals. Rather, it is obtained in readily available forms or is produced by the conversion of provitamins obtained through the diet. Retinyl esters and carotenoids are the two dietary precursors of retinol. These conversions take place in the lumen and mucosal cells of the intestine, and specific enzymes are involved in it.21 A brief description of these synthetic reactions is given below:

  • From Retinyl Esters

The retinyl esters, obtained from the animal foods, are directly converted into all-trans-retinol, in the intestine, through hydrolysis by an enzyme, hydrolase.21

  • From β-carotene

Retinol is also synthesized from the carotenoids especially β-carotene that is obtained from the fruits and vegetables containing yellow, orange, and dark green pigments. Moore was the first person who proved that β-carotene was metabolized and converted into retinol in animals.22 Unlike retinyl esters, this conversion occurs in a series of reactions. The first step is a dioxygenase reaction in which a molecule of oxygen reacts with the central two carbon atoms of β-carotene.23 During this reaction, the central double bond is cleaved generating an epoxide. It is catalyzed by the enzyme β-carotene 15-15’-monooxygenase. Water reacts with the epoxide and produces two hydroxyl groups which are then reduced to aldehydes. The compound that is formed as a result of this cleavage is known as retinal, and it contains an aldehyde functional group attached at one end.24

In the next step, the retinol dehydrogenase enzyme causes the reduction of retinal utilizing NADH, and retinol is produced, as a consequence. 21, 23

Synthesis of Retinol in Body

The biosynthesis of retinol from retinyl esters and β-carotène is shown in figure 21.

Transport, Storage, and Utilization of Retinol in Body


After the formation of free retinol, it is bound to the cellular Retinol Binding Protein (RBP-1) in the intestinal mucosal cells. The enzyme lecithin: retinol acyltransferase (LRAT) re-esterifies it with long chains of saturated fatty acids to produce esters. 25 The resulting retinyl esters are then incorporated into the hydrophobic core of chylomicrons along with other neutral lipid esters including triacylglycerols, phospholipids, apolipoprotein B, free cholesterol, and cholesteryl esters.26 These chylomicrons containing retinyl esters are then released into the lymph. After passing through the thoracic and other lymphatic ducts, they eventually enter the blood circulation.26 

While in circulation, chylomicrons are converted into “chylomicrons remnants”. It occurs due to the hydrolysis of triacylglycerol, by lipoprotein lipases present in the extrahepatic tissues.27 The liver has a high affinity towards these chylomicrons remnants, and it causes their uptake from the blood into hepatic cells.28 Some experts believe that retinyl esters are broken down by hydrolysis and re-esterified by LRAT, during this uptake by the liver.


95% of the retinol is stored in the liver in the form of retinyl esters chiefly as retinyl palmitate and retinyl stearate. This makes the liver the major site of storage of retinol (Vitamin A1). 29, 30 After the exclusive uptake by the hepatocytes, retinyl esters are then majorly (~80% of total) transferred to and stored in the stellate cells present around the sinusoidal spaces of the liver.29, 31 


When the concentration of vitamin A falls in the body, retinyl esters stored in the liver are mobilized. They are hydrolyzed into free retinol which binds with serum Retinol Binding Protein (RBP4) in the endoplasmic reticulum and is transported to the peripheral tissues of the body.32 Retinol is converted into its two primary biologically active forms i.e. 11-cis retinaldehyde and all-trans retinoic acid. These metabolites are then utilized for various purposes in different tissues and organs of the body.33

Functions of Retinol in Biological System

Retinol and its active metabolites are vital for the normal development, and functional maintenance of the human body. They are needed at every point in life, from embryogenesis to old age.1, 2 A detailed description of these biological functions of retinol is given below.

Organogenesis during Embryological Life

Developmental abnormalities were reported in the babies of those animals who were fed with a vitamin A-deficient diet.  This developed the idea that Vitamin A was required for normal embryonic development.34 Retinol is transported from mother to the fetus by two pathways, either through the transfer of maternal retinol to the fetal RBP4 (Retinol Binding Protein) or in the form of circulating retinyl esters across the placenta. 35, 36 This transported retinol is essential for the development of the following organs and organ systems in the fetus.

  • Nervous System

Retinol plays an important role in various aspects of nervous system development like patterning, and differentiation of neurons, etc.37, 38 For instance, retinoic acid, an active metabolite of retinol, contributes to the anteroposterior patterning of the neural plate during the development of the hindbrain.39 Hindbrain develops 8 transient segments, called rhombomeres, each of which has specific properties, and Homeobox (Hox) gene expression. In the absence of Retinoic acid, the last four rhombomeres fail to develop due to the interruption of this Hox signaling pathway.40

  • Eye 

Initially, it was hypothesized that retinoic acid was involved in the patterning of the retina, but the idea was rejected due to a lack of supporting evidence. Instead, the retinoic acid synthesized, from retinol, in the retina is secreted in the surrounding perioptic mesenchyme. Here, it acts in a paracrine fashion to prevent mesenchymal overgrowth and promotes normal development of anterior eye structures. In its absence, the signaling pathway and gene expression, controlling the apoptosis of mesenchymal cells, are disturbed resulting in congenital eye defects. 41, 42

  • Heart

Retinol is also essential for many important events in mammalian heart development, like patterning and looping of heart tube; septation of heart chambers and their outflow tracts; differentiation of heart muscle cells; ventricular trabeculations; and formation of coronary blood vessels, etc. 43, 44, 45

  • Other organs 

Along with the formation of new somites from the presomitic mesoderm, vitamin A is also involved in the normal development of the skeleton. 46, 47 Besides this, retinol and its active metabolites are vital for the organogenesis of the diaphragm, upper respiratory tract, lungs, kidneys, pancreas, and limbs. Its deficiency causes congenital diaphragmatic hernia; agenesis of the esophagotracheal septum, and lungs; embryonic renal hypoplasia; abnormal limbs, etc. 48, 49, 50, 51, 52

Maintenance of Normal Vision

The most well-known function of retinol (Vitamin A) is vision. It is transported to the pigmented epithelium of the retina. Here, RPE65 (Retinal pigment epithelium-specific 65 kDa) protein and other enzymes are present which convert it into 11-cis-retinal through a series of reactions. 11-cis-retinal is then transported into rod cells (photoreceptor cells of the retina), where it combines with opsin protein to generate ‘rhodopsin’. Rhodopsin is the visual pigment that detects a small amount of light making it essential for night vision. 53

Whenever light falls, the shape of rhodopsin changes due to the transformation of 11-cis-retinal into all-trans-retinal. This configurational change triggers a cascade of events that generates an electrochemical signal in the optic nerve. The signal is transmitted to the brain which interprets it as vision. 53

Gene Expression and  Stem Cell differentiation

Vitamin A regulates gene expression as we have discussed above in organogenesis. Retinol is taken up by the cells where it is oxidized into retinal which is further oxidized into retinoic acid. Retinoic acid is a very potent molecule and tends to initiate or inhibit the expression of genes by binding with different nuclear receptors.54 It also causes unsequestering of specific genomic sequences; thus, making the cells more committed to their fate. In other words, it plays an integral role in the differentiation of stem cells into cells of different lineages. 55

Maintenance of Skin Health

Retinol and its derivatives promote the proliferation of keratinocytes; prevent the transepidermal loss of water; fortify the protective role of the epidermis; induces the synthesis of collagen fibers and reduces their degradation; inhibit the activity of metalloproteinases, etc.56 In this way, retinol slows down the aging process in the skin and maintains its normal health and appearance.

These various anti-aging effects of retinol on skin and their mechanism are discussed later in detail under the section of ‘Cosmetic Use – Anti-aging effects of Retinol’


Retinol (Vitamin A) is needed for normal reproduction in both males and females.2

  • Male reproduction

Retinol metabolites specifically retinoic acid are required for both the differentiation of adult males’ spermatogonia and their entrance into meiosis.57 Experimental studies have shown that vitamin A deficiency not only ceases spermatogenesis but also causes squamous metaplasia of the epithelium of epididymis, seminal vesicles, and prostate gland in males.58, 59 

  • Female Reproduction

Retinol is necessary for normal fertilization, implantation, and early embryogenesis.60 In vivo studies have presented clear evidence that it is essential for the normal onset of meiotic prophase in germ cells of female ovaries. 61 Maternal retinol is also involved in the development and maintenance of the placenta. 62 

Development and Maintenance of the Immune system

  • Skin

The first thing that hinders the entry of infectious agents, is the skin. It makes skin the first line of defense of the body against invading pathogens. Retinol and its metabolites maintain the integrity and functionality of skin and mucosal cells lining the air passages, gastrointestinal and urinary tracts (common sites of microbes’ invasion). 63 Thus, it is one way of how retinol takes part in maintaining the immunity of the body.

  • White Blood Cells

Retinoids are involved in the differentiation and normal functioning of white blood cells including neutrophils, lymphocytes, and macrophages, etc. They also cause the production of cytokines that induces the synthesis and recruitment of immune cells of the body. 64

Iron metabolism and RBCs Formation

Retinol metabolites regulate the normal metabolism of iron. For instance, they facilitate the mobilization of iron from its storage sites and deliver it to the developing red blood cells for integration into hemoglobin, the oxygen-carrying protein. 65, 66 Apart from this, they also promote the differentiation of precursor stem cells into erythrocytes (Red blood cells).67 Thus, iron metabolism and hematopoiesis are dependent upon vitamin A. 


The growth of the body is mediated by the release of somatotropin, also known as the Human Growth Hormone, from the pituitary gland of the brain. Studies have demonstrated that levels of vitamin A are directly related to the production of this growth hormone.68

Glycoprotein Synthesis

Adequate availability of retinol is required for the synthesis of glycoproteins in the body.69 In its absence, glycoprotein synthesis is arrested, and it also increases the risk of corneal ulcerations.70

Reduces Risks of Cancer

Retinol and its derivatives have antioxidative, proapoptotic, anti-proliferative, and differentiation effects.71 Therefore, they act as chemotherapeutic and cancer-preventing agents that decrease the incidence of different kinds of cancers by causing the differentiation, apoptosis, and growth arrest of tumor cells.72 Studies have shown that natural and synthetically-derived retinoids are effective in preventing the development and progression of tumors, like skin, oral cavity, lung, liver, breast, gastrointestinal, bladder, and prostatic cancers.73, 74, 75


Sources of Retinol

Retinol can be obtained through diet and is also available in the market in the form of synthetic supplements. 

Dietary sources

Retinol or Vitamin A1 is present only in foods of animal origin. The major foods that are rich in retinol are mentioned below and each of them contains 150 mg of retinoids in per 1.75 – 7 oz (50 – 198 g)

  • Meat 
  • Liver (beef, fish, turkey, chicken, pork)
  • Cod liver Oil
  • Eggs
  • Cheese
  • Milk
  • Butter
  • Fish like salmon, tuna, shellfish – etc 76, 77

Moreover, as we have discussed earlier that provitamins, including retinyl esters and carotenoids, are converted into Vitamin A1 in the body, foods containing these provitamins are also an indirect source of retinol. These foods include:

  • Dark green and leafy vegetables
  • Red and orange fruits, flowers, and juices
  • Red and yellow vegetables, like carrots 
  • Tubers, like sweet potato
  • Algae
  • Red palm oil – etc  78

Synthetic Sources

Due to numerous health benefits and the prevalence of vitamin A deficiency in people, specifically in developing countries, retinol is also artificially synthesized commercially. These retinol supplements are been sold under different trading names like Acon, Afaxin, Agiolan, Alphalin, Anatola, Aoral, Apexol, Apostavit, Atav, Avibon, Avita, Avitol, Axerol, Dohyfral A, Epiteliol, Nio-A-Let, Prepalin, Testavol, Vaflol, Vi-Alpha, Vitpex, Vogan, and Vogan-Neu.


Units of Measurement

International Units (IU)

When addressing the nutritional science, or talking about how much retinol one should take in a day i.e. Recommended Daily Allowance, retinol is usually measured in terms of International Units (IU). Approximately, 0.3 micrograms (300 nanograms) of retinol are equivalent to 1 IU. 

Retinol Equivalents (RE) 

However, as mentioned above, retinol is also obtained from foods, in different provitamin forms like β-carotene. That’s why the amount of retinol is also measured in terms of Retinol Equivalents (RE). 1 RE is equal to 0.001 milligrams (1microgram) of retinol, or 0.006 milligrams (6 micrograms) of β-carotene, while 3.3 International Units of vitamin A make 1 RE equivalence. 

Retinol Activity Equivalents (RAE)

RAE is the new recommended unit for the measurement of retinol. It replaces the older Retinol Equivalent (RE), and better takes into consideration the variable absorption and conversion of retinol and provitamins-A carotenoids, by the human body. New Nutrition Facts and Supplement Facts Labels mention Vitamin A in terms of µg RAE. Recently, the U.S. Food and Drug Administration (FDA) has also issued new guidelines and directed the manufacturers to use RAE units while labeling. 79

1 µg RAE is equivalent to 1 µg retinol, 2 µg beta-carotene obtained through supplements, 12 µg of dietary β-carotene, 24 µg of dietary α-carotene, or 24 µg of β-cryptoxanthin. 80


Recommended Dietary Intake:

According to the Institute of Medicine (IOM), for an average male with 25 years of age, the Recommended Dietary Allowance (RDA) is 900 µg RAE (3000 IU) per day, while it is 700 µg RAE in the case of females of the same age. National Health Service (NHS), United Kingdom, however, recommends a bit lower RDA i.e. 700 µg RAE for men and 600 µg RAE for women.81 Pregnant females need slightly higher amounts, while the lactating females should take relatively more Vitamin A per day to meet their demands as well as their baby’s. The complete description of Recommended Dietary Allowances (RDA) values for individuals of different age is given in table 1. 80

Table 1: Recommended Dietary Allowances (RDAs) for Retinol / Vitamin A 

0–6 months400 µg RAE400 µg RAE  
7–12 months500 µg RAE500 µg RAE  
1–3 years300 µg RAE300 µg RAE  
4–8 years400 µg RAE400 µg RAE  
9–13 years600 µg RAE600 µg RAE  
14–18 years900 µg RAE700 µg RAE750 µg RAE1,200 µg RAE
19–50 years900 µg RAE700 µg RAE770 µg RAE1,300 µg RAE
51+ years900 µg RAE700 µg RAE  

Disorders Associated with Over-intake of Retinol

Just like the inadequate intake of retinol poses risks of various health abnormalities, its over-intake is also harmful to the body. Both for the average male and female with 25 years of age, the Tolerable Upper Intake Level (UL) of retinol is 3,000 µg (10,000 IU) per day. The ULs for individuals of different ages and statuses are given in the table.

Table: Tolerable Upper Intake Levels (ULs) for Retinol80

0–12 months600 µg600 µg  
1–3 years600 µg600 µg  
4–8 years900 µg900 µg  
9–13 years1,700 µg1,700 µg  
14–18 years2,800 µg2,800 µg2,800 µg2,800 µg
19+ years3,000 µg3,000 µg3,000 µg

3,000 µg

Problems associated with excess intake of retinol include

Hypervitaminosis A

As extra retinol is stored in the liver, too much consumption of preformed retinol in the diet leads to its accumulation up to toxic levels that can prove fatal. The condition is known as hypervitaminosis A.82 It occurs due to over-consumption of retinyl esters (obtained from animal foods), specifically, the liver of animals living in polar areas like seals, polar bears, etc.83, 84 It does not happen in the case of carotenoids, like β-carotene, because its conversion into retinol is done as per the needs of the body. 85 The toxicity can be acute or chronic, each having different manifestations.

    • Acute toxicity

Acute toxicity occurs within a few hours or days after the consumption of heavy doses of Vitamin A in the form of foods or supplements. Acute hypervitaminosis A typically presents with nausea, vomiting, and diarrhea, followed by central nervous symptoms like irritability, drowsiness, and rarely convulsions, or coma.86

    • Chronic toxicity

 Chronic cases happen when doses more than RDA are being taken for prolonged periods. It manifests mainly as musculoskeletal problems, fatigue, loss of appetite, weight loss, skin changes, blurred vision, hepatomegaly, and may lead to coma and death.4, 87


Research data has shown that excess retinol /vitamin A induces bone resorption and prevents bone formation. It results in bone loss and osteoporosis. It may occur even at relatively lower concentrations than are required for developing toxicity i.e. with unappreciated hypervitaminosis A. 88

Birth defects

During pregnancy, vitamin A should be taken just according to the Recommended Dietary Allowance (RDA) as both deficiency and excessive consumption can lead to serious birth defects in babies. Congenital abnormalities, due to retinol intake exceeding UL, include malformations of eye, lungs, heart, head, limbs, etc. 89, 90 The U.S. Food and Drug Administration (FDA) suggests that pregnant women should obtain their vitamin A from β-carotene containing foods, and the consumption of retinol/retinyl esters should be no more than 5,000 IU.

Hair Loss

According to several research studies, it has been observed that patients having hypervitaminosis A also develop hair loss problems. 91, 92


Disorders due to Inadequate Intake of Retinol

An adequate amount of retinol is necessary for embryogenesis, and its deficiency results in congenital birth defects (described above). Other disorders related to retinol insufficient intake are:

Night blindness

Night blindness is the most common manifestation of vitamin A deficiency. It is an inability to see properly in dim light. The role of retinol in the formation of light-sensitive pigment, rhodopsin, has been discussed above. When light falls on rhodopsin, it breaks to generate opsin and all-trans-retinal. Through a series of reactions, collectively known as the “Visual Cycle”, all-trans-retinal is converted into 11-cis-retinal that is required for regeneration of rhodopsin. Adequate amounts of retinol in the body are required for this regeneration process. As rhodopsin is responsible for the vision in dim light; therefore, insufficient intake of retinol results in night blindness. 93

Keratomalacia and Xerophthalmia

Due to the lower intake of retinol, the cornea of the eye becomes cloudy and dry, a condition is known as keratomalacia. This causes difficulty in vision. It also increases the risk of corneal ulceration and bacterial infections.  A similar condition is a xerophthalmia in which eyes become dry due to the absence of tear production, and vitamin A deficiency is the basic etiology behind it. 94, 95

Brittle Nails and Dry skin

Inadequate intake of retinol can also present as cutaneous manifestations. Clinical data proves that patients with vitamin A deficiency also show symptoms of brittle nails, dry, harsh, and goose-like skin, sometimes along with papular eruptions. 96


Groups at Risk of Developing Deficiency

Although retinol or Vitamin A is stored in the body, its daily intake is recommended by the health authorities. It is particularly essential for those groups of people who are at risk of developing Vitamin A deficiency. These include:

Premature Babies

At the time of birth, preterm infants do not have a sufficient amount of Vitamin A stored in their liver, and usually, the levels of retinol in their plasma also remain low throughout the first year of life.97 

Young Children and Infants

In developing countries, the prevalence of Vitamin A deficiency among young children increases as soon as they are shifted from breastfeeding.98 In developed countries, such cases are mostly seen in children with some malabsorptive disorders.99

Pregnant and Lactating Women

In pregnant as well as in lactating females, an extra amount of retinol is required for their baby growth and tissue maintenance, and also for their metabolism.100 That’s why; they can develop vitamin A deficiency if the amount they are taking is inadequate. 


Commercial Synthesis of Retinol

There are 4 major synthetic routes known that are used industrially to produce retinol. These include Organon, Hoffmann-La Roche, BASF, and Rhone-Poulenc synthesis.101 β-ionone is the fundamental starting material in the synthesis of retinol or Vitamin A, in all these major commercial synthetic routes. 102 Generally, in the industrial synthesis of retinol, the first retinal (aldehyde form of the vitamin) is produced through the reduction of a pentadiene compound. Succeeding acidification and hydrolysis of the retinal then generate retinol.

After the synthesis, extreme care is required as the pure form of retinol is highly responsive and susceptible to oxidation on exposure to atmospheric oxygen. That’s why its preparation and transportation is done at low temperatures and under an oxygen-free environment.


Cosmetic Use – Anti-aging effects of Retinol 

Retinol is excessively used in creams and many other skin products. It is the first-ever vitamin that is approved by the Food and Drug Administration (FDA) to be used as an anti-wrinkle substance that improves skin appearance and has anti-aging effects.

Mechanism of Action

On topical application, the fat-soluble retinol penetrates into the stratum corneum and other layers of the skin, and also slightly enters into the dermis. It promotes cellular activity in skin cells including keratinocytes, melanocytes, fibroblasts, and Langerhans cells. 56 Being a lipophilic molecule, it diffuses through the cell membrane and enters the cytoplasm where it binds with the Cytosolic Retinol-Binding Protein (CRBP). 103, 104 It is delivered to relevant enzymes that convert it into its active form i.e. retinoic acid, through oxidation.104

Retinoic acid is then transported to the nucleus by cytosolic RA-binding protein (CRABP), specifically by the CRABPII as it is the predominant binding protein in the skin.105 Inside the nucleus, retinoic acid binds to the nuclear RA receptor (RAR), Retinoid X Receptors (RXR), and fatty acid-binding protein 5,105 this RAR and RXR nuclear receptors have different subtypes including α, β, and ɣ receptors, and each subtype has further different isoforms. 104 Different topical retinoids have selective affinity towards particular subtypes.106 RAR-α and RXR-ɣ are the major subtypes present in human skin. 56

The binding of retinoic acid to the nuclear receptors leads to the formation of heterodimers of RAR and RXR, while RXR can also form homodimers.107 These dimer complexes in turn attach to specific DNA sequences present in the promoter gene region, which is also known as Retinoic Acid Response Element (RARE) or Retinoid Response Element (RRE). As a result, transcription of genes occurs that modulates cellular activity through a series of steps. The intracellular mechanism of retinol action in skin cells is shown in the figure.108

The various effects impart by the topical application of retinol on the skin are as follows:

  • Enhanced Collagen Synthesis

Human skin majorly contains type 1 collagen that plays an important role in the strength and stability of skin. Collagen I biosynthesis starts with the formation of procollagen I within fibroblast. 109 Studies have demonstrated that retinol derivatives increase the production of procollagen I by stimulating gene expression in fibroblasts.110 As a result, collagen synthesis is enhanced in the skin.

  • Reduced Collagen Degradation

Collagenase enzymes are responsible for the breakdown of collagen. Retinol induces tissue inhibitors of collagenases; thus, reduces the degradation of collagen in the skin.111

  • The proliferation of Epidermal Cells

With increasing age, the epidermis and dermis become thin due to a reduction in the number of epidermal keratinocytes and dermal stromal cells, respectively. 112, 113 Retinol increases the cellular turnover of the epidermis and enhances the proliferation of the basal layer of epidermal cells. 56 

AP-1 complex plays a central role in the proliferation of keratinocytes in response to cytokines, growth factors, and various other stimuli. It largely comprises a c-Jun/c-fos transcription factor. Studies have shown that topical use of retinol elevates this epidermis –specific c-Jun transcription factor which in turn stimulates the proliferation of keratinocytes.114

  • Induces Production of Extracellular Matrix (ECM)

The Transforming Growth Factor-β (TGF- β) pathway is the major mediator of the Extracellular Matrix (ECM) production by fibroblast present in the dermis. 115 It has been found that topical retinol significantly causes the increased production of TGF-β1 mRNA, and also down-regulates the Smad mRNA and protein that are potent inhibitors of TGF- β signaling. 114 Therefore, the upregulation of the TGF-β/CTGF (Connective Tissue Growth Factor) pathway in dermal fibroblasts by topical use of retinol enhances the production of ECM in the skin. 

  • Inhibition of Matrix Metalloproteinases

Matrix metalloproteinases (MMP) including collagenase, gelatinase, stromelysin-1, etc, are the enzymes that cause degradation of the components of the extracellular matrix. They are involved in UV-induced damage to the skin cells and are responsible for cellular aging.AP-1 and NF-κB transcription factors stimulate metalloproteinases’ gene expression. Studies have shown that the retinol derivative i.e. all-Trans retinoic acid causes transgression of AP-1 and reduces metalloproteinase synthesis.116 Moreover, it also enhances the production of tissue inhibitors of metalloproteinases. (TIMPS) 117

  • Regulation of Melanogenesis

Increased pigmentation of the skin is a common association of photoaging induced by the UV radiations present in sunlight. 118 It is caused by the poor regulation of the function of melanocytes as well as by the enhanced transfer of melanin to the epidermal cells.119 

Topical retinoids are found effective in the reduction of this hyperpigmentation up to 60%.56 They influence melanocytes’ functioning, block the transfer of melanin to keratinocytes, ensure the regular distribution of melanin in the epidermis of the skin, and also limit melanin content by increased turnover of epithelial cells.120 Further, it also upregulates the synthesis and activity of the tyrosinase enzyme that breaks tyrosine, a central component of melanogenesis. 56 In this way, it diminishes melanin formation.

  • Angiogenesis

Topical retinol stimulates the formation of new blood vessels in the papillary layer of the dermis. 114  it is believed that epidermal keratinocyte proliferation provides a favorable environment for angiogenesis. In fact, the keratinocytes are a good source of Vascular Endothelial Growth Factor (VEGF) which is a potent angiogenic agent. 121 Moreover, increase the production of ECM in the dermis is also reported to enhance the proliferation of the endothelial cells of blood vessels. 122

  • Other Effects

Retinol and its derivatives diminish the activity of enzymes involved in the process of lipogenesis, and also reduce the cellular divisions in sebocytes (sebum-producing epithelial cells). 14  Retinol hampers the shedding of cells within the ducts of sebaceous glands, and also downregulates sebum secretion; thus, minimizing the propensity of blackheads formation in the skin.123 Like other metalloproteinases, retinol also inhibits elastases and MMP-9 which are involved in the breakdown of elastin fibers. Therefore, by preventing the degradation of elastin fibers, and with increased elastin synthesis, it maintains the elasticity of the skin.124


Because of the above-mentioned effects of retinol on the skin, the topical use of retinol-containing products has many benefits. These include:

  • Wrinkle-free skin

Retinol tightens the skin through the production of more new cells. This helps in the removal of wrinkles from and aged skin and makes it smooth.

  • Elasticity

Elastin fibers render elasticity to the skin. As retinol enhances the synthesis of elastin fibers and reduces its degradation by down-regulating the activity of elastases and other metalloproteinases, topical retinol decrease skin fragility and make it elastic.

  • Skin Brightening

Another benefit is the removal of sunspots and the fading of UV-induced hyperpigmented. Due to excessive cell turnover, retinol promotes the removal of excess melanin from the skin. Moreover, it also decreases the production and distribution of new melanin. Therefore, retinol skin-care products are renowned for skin brightening.

  • Clear and Less Oily Skin

As described above, retinol regulates the secretion of sebum from the sebaceous glands and minimizes the chances of blackheads formation. It makes the skin clear and less oily.

  • Imparts Strength 

Due to the enhanced production of collagen fibers with minimal degradation, topical retinol decreases the fragility of aged skin and imparts its strength.

  • Skin homeostasis

Epidermal thinning and reduced vasculature cause the skin to become fragile, and wound healing also becomes poor. 125 Topical retinol increases the vascularity of skin and epidermal cells’ proliferation; thus provides a more suitable environment for skin homeostasis. 114


Creams and other skin-care products containing retinol are used externally for various purposes. For instance, they are used for skin conditions like acne vulgaris, psoriasis, skin keratosis, etc. 126, 127, 128 They are also used for hair and nail disorders.56 Retinol derivatives are very effective in reducing inflammation of hair follicles and sebaceous glands. Moreover, people use them for photoprotection from sunlight, and also apply them on hyperpigmented and photo-damaged skin. 129

Side Effects

Where there are numerous benefits of topical retinol, few side effects also may occur. Mostly, it is due to excessive use of retinol in high doses for a prolonged period of time. These include;

  • Contact Dermatitis

In some people, the skin may be sensitive to retinol, and becomes red (Retinoid-flare), swollen, and itchy on its topical application resulting in contact dermatitis.130

  • Eczema and Pruritis

Eczema and Pruritis are skin conditions in which there are severe itching and irritation of the skin. They may also occur as side effects of retinol. 131

  • Epidermal Hyperplasia

Studies have shown that tropical can cause epidermal hyperplasia in the skin as it increases the proliferation of skin cells.132

  • Skin Discoloration

Prolong and excessive use of retinol containing products can also lead to skin discoloration.131

Therapeutic uses

Retinol is clinically used for many purposes. It is also included in the List of Essential Medicines given by the World Health Organization (WHO). It is an Over-the-counter drug that means no doctor’s prescription is needed to buy it, and it is readily available in pharmaceutical stores. The mode of administration is either through the mouth or through intramuscular injection. The clinical data, legal status, and identification tags are mentioned in the table:

Clinical data
License dataUS DailyMedRetinol
US: X (Contraindicated) 
Routes of
by mouth, Intramuscular Injection
Drug classvitamin
Legal status
Legal statusUS: OTC
IUPAC name
  • (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol
CAS Number68-26-8
PubChem CID1071
CompTox Dashboard (EPA)DTXSID3023556 
ECHA InfoCard100.000.621 

Retinol and provitamin-A supplements are being used to treat many health abnormalities. These uses are described below:

Vitamin A deficiency

As described above, a lower dietary intake of Vitamin A and its derivates causes its deficiency and leads to various health problems.7, 8 Retinol and its supplements can be clinically given to susceptible people or those who are deficient, to meet the body demands of Vitamin A and to prevent the resulting health disorders.  Three strategies may be used in this regard:133

  • Diet adjustment

Retinol and provitamin A-rich sources of foods are adjusted in the diet plan of the affected individuals.

  • Fortification

In this, the synthetic retinol or Vitamin A is added while the preparation and processing of commonly eaten foods, like bread, cereals, flour, and baby’s formula feed, etc.

  • Supplementation

High dose supplements may be given to treat the deficiency effectively.


Like we have discussed earlier that retinol and its metabolites play important roles in gene expression, and also have antioxidant, anti-proliferating, and differentiation-inducing properties, they can be effective in preventing or treating cancers.54, 71, 72 For example, daily ingestion of retinol in larger amounts helps prevent Squamous Cell Carcinoma (SCC) of the skin.134

However, this association between higher vitamin A intake and cancer risk is still unclear because research studies have shown mixed kinds of results. For instance, some studies demonstrated that taking more amounts of carotenoids and retinol-enriched supplements lowers the risk of lung cancer. 135 While, on the other hand, those researches can also be found which claim the opposite i.e. higher intake increases the possibilities of developing lung cancer. 136, 137 Same is the case with prostate cancer. 138, 139


Measles is one of the major diseases of young children in developing countries, and according to an estimate, 900,000 deaths are ensued every year due to measles in these countries. 140 Vitamin A deficiency is also recognized as the risk factor of severe measles.141 Therefore, supplementation of retinol and its metabolites is done to reduce the mortality and morbidity in children with measles. Even, big health authorities like World Health Organization, have recommended that children, who are older than 1 year of age and are living in those areas where vitamin A deficiency is prevalent, should be given high doses of vitamin A (around 200,000 IU or 60,000 µg RAE) orally for two consecutive days.142

Age-related Macular Degeneration

Age-related Macular Degeneration (AMD) is one of the principal causes of blindness among seniors age above 65. Despite numerous research studies, the precise etiology of AMD is still unknown. 143 However, it is thought that like other old-age health disorders, AMD is also because of the cellular damage due to oxidative stress of Reactive Oxygen Species (ROS).144 That’s why; the effectiveness of nutritional antioxidants in treating AMD is being evaluated. 144 Several studies have demonstrated that people taking carotenoids supplements including beta-carotene, lutein, and zeaxanthin, have significantly lower risks of developing advanced AMD as compared to those in the control group. 145

Drug Interactions of Retinol

Certain drug interactions between retinol and other medications have been reported. For instance, Orlistat (Alli®, Xenical®), used for weight reduction, decreases the absorption of retinol and other fat-soluble vitamins. Similarly, synthetic retinoids like Aciterin (Soriatane®) and Bexarotene (Targetin®), used for the treatment of psoriasis, when taken along with vitamin A supplements, can cause hypervitaminosis A. Therefore, one should consult a doctor before taking retinol supplements if he/she is already on meds.


  1. Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annual review of nutrition. 2002 Jul;22(1):347-81
  2. Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011 Apr;3(4):385-428.
  3. US Food and Drug Administration. Fortify your knowledge about vitamins. US Food and Drug Administration: Silver Spring, MD, USA. 2009.
  4. Office of Dietary Supplements – Vitamin A [Internet]. 2020 [cited 2020Sep1]. Available from:
  5. O’Byrne SM, Blaner WS. Retinol and retinyl esters: Biochemistry and physiology Thematic Review Series: Fat-soluble vitamins: vitamin A. Journal of lipid research. 2013 Jul 1;54(7):1731-43.
  6. Valla AR, Cartier DL, Labia R. Recent Progress in Retinoid Chemistry. InStudies in Natural Products Chemistry 2003 Jan 1 (Vol. 28, pp. 69-107). Elsevier.
  7. Dowling JE, Wald G. Vitamin A deficiency and night blindness. Proceedings of the National Academy of Sciences of the United States of America. 1958 Jul 15;44(7):648.
  8. Singh V, West KP. Vitamin A deficiency and xerophthalmia among school-aged children in Southeastern Asia. European Journal of Clinical Nutrition. 2004 Oct;58(10):1342-9.
  9. Whiting SJ, Lemke B. Excess retinol intake may explain the high incidence of osteoporosis in northern Europe. Nutrition reviews. 1999 Jun 1;57(6):192. 
  10. Carpenter TO, Pettifor JM, Russell RM, Pitha J, Mobarhan S, Ossip MS, Wainer S, Anast CS. Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake. The Journal of pediatrics. 1987 Oct 1;111(4):507-12.
  11. Baglin A, Hagege C, Franc B, Richaud M, Prinseau J. A systemic-like disease: chronic vitamin A poisoning. InAnnales de Medecine Interne 1986 Jan 1 (Vol. 137, No. 2, pp. 142-146).
  12. Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. New England Journal of Medicine. 1995 Nov 23;333(21):1369-73.
  13. Semba RD. On the ‘discovery’ of vitamin A. Annals of nutrition and metabolism. 2012;61(3):192-8.
  14. Wolf G. Discovery of vitamin A. e LS. 2001 May 30.
  15. Squires VR, editor. The Role of Food, Agriculture, Forestry and Fisheries in Human Nutrition-Volume III. EOLSS Publications; 2011 Nov 15.
  16. Retinol [Internet]. Chemistry Explained. [cited 2020Sep1]. Available from:
  17. Vitamin A [Internet]. Cameo Chemicals. [cited 2020Sep2]. Available from:
  18. Vitamin A [Internet]. DrugBank. 2020 [cited 2020Sep2]. Available from:
  19. National Center for Biotechnology Information. PubChem Compound Summary for CID 445354, Retinol. [Internet]. 2020 [cited 2020Sep2]. Available from:
  20. Showing metabocard for Vitamin A (HMDB0000305) [Internet]. Human Metabolome Database. [cited 2020Sep2]. Available from:
  21. Homo sapiens retinol biosynthesis [Internet]. 2020 [cited 2 September 2020]. Available from:
  22. Moore T. The Conversion of Carotene to Vitamin A in vivo. Biochem. J.. 1930;24:696-702.
  23. GOODMAN DS. Biosynthesis of Vitamin A from β-Carotene. The American Journal of Clinical Nutrition. 1969 Jul 1;22(7):963-5.
  24. Dewick PM. Medicinal natural products: a biosynthetic approach. John Wiley & Sons; 2002 Jan 3.
  25. O’Byrne SM, Wongsiriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, Palczewski K, Blaner WS. Retinoid absorption and storage is impaired in mice lacking lecithin: retinol acyltransferase (LRAT). Journal of Biological Chemistry. 2005 Oct 21;280(42):35647-57.
  26. Harrison EH. Mechanisms of digestion and absorption of dietary vitamin A. Annu. Rev. Nutr.. 2005 Jul 11;25:87-103.
  27. Hussain MM, Kancha RK, Zhou Z, Luchoomun J, Zu H, Bakillah A. Chylomicron assembly and catabolism: role of apolipoproteins and receptors. Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism. 1996 May 20;1300(3):151-70.
  28. Blomhoff R, Helgerud P, Rasmussen M, Berg T, Norum KR. In vivo uptake of chylomicron [3H] retinyl ester by rat liver: evidence for retinol transfer from parenchymal to nonparenchymal cells. Proceedings of the National Academy of Sciences. 1982 Dec 1;79(23):7326-30.
  29. Matsuura T, Gad MZ, Harrison EH, Ross AC. Lecithin: retinol acyltransferase and retinyl ester hydrolase activities are differentially regulated by retinoids and have distinct distributions between hepatocyte and nonparenchymal cell fractions of rat liver. The Journal of nutrition. 1997 Feb 1;127(2):218-24.
  30. Harrison EH, Blaner WS, Goodman DS, Ross AC. Subcellular localization of retinoids, retinoid-binding proteins, and acyl-CoA: retinol acyltransferase in rat liver. Journal of Lipid Research. 1987 Aug 1;28(8):973-81.
  31. Sporn MB, editor. The retinoids. Academic Press; 2012 Dec 2.
  32. Shirakami Y, Lee SA, Clugston RD, Blaner WS. Hepatic metabolism of retinoids and disease associations. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2012 Jan 1;1821(1):124-36.
  33. Harrison EH. Mechanisms of transport and delivery of vitamin A and carotenoids to the retinal pigment epithelium. Molecular nutrition & food research. 2019 Aug;63(15):1801046.
  34. Hale F. Pigs born without eye balls. InProblems of birth defects 1933 (pp. 166-167). Springer, Dordrecht.
  35. Quadro L, Hamberger L, Gottesman ME, Wang F, Colantuoni V, Blaner WS, Mendelsohn CL. Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency. Endocrinology. 2005 Oct 1;146(10):4479-90.
  36. Quadro L, Hamberger L, Gottesman ME, Colantuoni V, Ramakrishnan R, Blaner WS. Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester. American Journal of Physiology-Endocrinology and Metabolism. 2004 May;286(5):E844-51.
  37. Clagett‐Dame M, McNeill EM, Muley PD. Role of all‐trans retinoic acid in neurite outgrowth and axonal elongation. Journal of neurobiology. 2006 Jun;66(7):739-56.
  38. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Reviews Neuroscience. 2007 Oct;8(10):755-65.
  39. Glover JC, Renaud JS, Rijli FM. Retinoic acid and hindbrain patterning. Journal of neurobiology. 2006 Jun;66(7):705-25.
  40. Maden M, Gale E, Kostetskii I, Zile M. Vitamin A-deficient quail embryos have half a hindbrain and other neural defects. Current biology. 1996 Apr 1;6(4):417-26.
  41. Molotkov A, Molotkova N, Duester G. Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning. Development. 2006 May 15;133(10):1901-10.
  42. Matt N, Ghyselinck NB, Pellerin I, Dupé V. Impairing retinoic acid signalling in the neural crest cells is sufficient to alter entire eye morphogenesis. Developmental biology. 2008 Aug 1;320(1):140-8.
  43. Hoover LL, Burton EG, Brooks BA, Kubalak SW. The expanding role for retinoid signaling in heart development. TheScientificWorldJOURNAL. 2008 Feb 25;8.
  44. Wagner M, Siddiqui MA. Signal transduction in early heart development (II): ventricular chamber specification, trabeculation, and heart valve formation. Experimental Biology and Medicine. 2007 Jul;232(7):866-80.
  45. Lin SC, Dollé P, Ryckebüsch L, Noseda M, Zaffran S, Schneider MD, Niederreither K. Endogenous retinoic acid regulates cardiac progenitor differentiation. Proceedings of the National Academy of Sciences. 2010 May 18;107(20):9234-9.
  46. Aulehla A, Pourquié O. Signaling gradients during paraxial mesoderm development. Cold Spring Harbor perspectives in biology. 2010 Feb 1;2(2):a000869.
  47. See AW, Kaiser ME, White JC, Clagett-Dame M. A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development. Developmental biology. 2008 Apr 15;316(2):171-90.
  48. Montedonico S, Nakazawa N, Puri P. Congenital diaphragmatic hernia and retinoids: searching for an etiology. Pediatric surgery international. 2008 Jul 1;24(7):755-61.
  49. Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. American Journal of Anatomy. 1953 Mar;92(2):189-217.
  50. Martín M, Gallego-Llamas J, Ribes V, Kedinger M, Niederreither K, Chambon P, Dollé P, Gradwohl G. Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Developmental biology. 2005 Aug 15;284(2):399-411.
  51. Lelièvre-Pégorier M, Vilar J, Ferrier ML, Moreau E, Freund N, Gilbert T, Merlet-Bénichou C. Mild vitamin A deficiency leads to inborn nephron deficit in the rat. Kidney international. 1998 Nov 1;54(5):1455-62.
  52. Stratford T, Logan C, Zile M, Maden M. Abnormal anteroposterior and dorsoventral patterning of the limb bud in the absence of retinoids. Mechanisms of development. 1999 Mar 1;81(1-2):115-25.
  53. Olson JA. Vitamin A. Handbook of vitamins. 2001 Apr 4;3:1-50.
  54. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. Journal of lipid research. 2002 Nov 1;43(11):1773-808.
  55. Soprano DR, Teets BW, Soprano KJ. Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells. Vitamins & hormones. 2007 Jan 1;75:69-95.
  56. Zasada M, Budzisz E. Retinoids: Active molecules influencing skin structure formation in cosmetic and dermatological treatments. Advances in Dermatology and Allergology/Postȩpy Dermatologii i Alergologii. 2019 Aug;36(4):392.
  57. Soprano DR, Teets BW, Soprano KJ. Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells. Vitamins & hormones. 2007 Jan 1;75:69-95.
  58. Wolbach SB, Howe PR. Tissue changes following deprivation of fat-soluble A vitamin. The Journal of experimental medicine. 1925 Dec 1;42(6):753-77.
  59. Mason KE. Differences in testis injury and repair after vitamin A‐deficiency, vitamin E‐deficiency, and inanition. American Journal of Anatomy. 1933 Mar;52(2):153-239.
  60. Thompson JN, Howell JM, Pitt GA. Vitamin A and reproduction in rats. Proceedings of the Royal Society of London. Series B. Biological Sciences. 1964 Feb 18;159(976):510-35.
  61. Li H, Clagett-Dame M. Vitamin A deficiency blocks the initiation of meiosis of germ cells in the developing rat ovary in vivo. Biology of reproduction. 2009 Nov 1;81(5):996-1001. 
  62. Howell JM, Thompson JN, Pitt GA. Histology of the lesions produced in the reproductive tract of animals fed a diet deficient in vitamin A alcohol but containing vitamin A acid. Reproduction. 1964 Apr 1;7(2):251-8.
  63. McCullough FS, Northrop-Clewes CA, Thurnham DI. The effect of vitamin A on epithelial integrity. Proceedings of the Nutrition Society. 1999 May;58(2):289-93.
  64. Semba RD. Impact of vitamin A on immunity and infection in developing countries. InPreventive Nutrition 1997 (pp. 337-350). Humana Press, Totowa, NJ.
  65. Lynch SR. Interaction of iron with other nutrients. Nutrition Reviews. 1997 Apr 1;55(4):102-10.
  66. Gropper SS, Smith JL. Advanced nutrition and human metabolism. Cengage Learning; 2012 Jun 1.
  67. Oren T, Sher JA, Evans T. Hematopoiesis and retinoids: development and disease. Leukemia & lymphoma. 2003 Jan 1;44(11):1881-91.
  68. Raifen R, Altman Y, Zadik Z. Vitamin A levels and growth hormone axis. Hormone Research in Paediatrics. 1996;46(6):279-81.
  69. Wolf G, Kiorpes TC, Masushige S, Schreiber JB, Smith MJ, Anderson RS. Recent evidence for the participation of vitamin A in glycoprotein synthesis. InFederation proceedings 1979 Oct 1 (Vol. 38, No. 11, pp. 2540-2543).
  70. Starck T. Severe Corneal Ulcerations and Vitamin A Deficiency. InAdvances in Corneal Research 1997 (pp. 557-567). Springer, Boston, MA.
  71. Doldo E, Costanza G, Agostinelli S, Tarquini C, Ferlosio A, Arcuri G, Passeri D, Scioli MG, Orlandi A. Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins. BioMed research international. 2015 Mar 24;2015.
  72. Niles RM. Signaling pathways in retinoid chemoprevention and treatment of cancer. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2004 Nov 2;555(1-2):97-105.
  73. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nature Reviews Cancer. 2001 Dec;1(3):181-93. 
  74. Arrieta O, González-De la Rosa CH, Aréchaga-Ocampo E, Villanueva-Rodríguez G, Cerón-Lizárraga TL, Martínez-Barrera L, Vázquez-Manríquez ME, Ríos-Trejo MÁ, Álvarez-Avitia MÁ, Hernández-Pedro N, Rojas-Marín C. Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010 Jul 20;28(21):3463-71. 
  75. Bryan M, Pulte ED, Toomey KC, Pliner L, Pavlick AC, Saunders T, Wieder R. A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer. Investigational new drugs. 2011 Dec 1;29(6):1482-7. 
  76. Brown JE. Nutrition now. Cengage Learning; 2012 Dec 13.
  77. Booth SL, Johns T, Kuhnlein HV. Natural food sources of vitamin A and provitamin A. Food and Nutrition Bulletin. 1992 Mar;14(1):1-5.
  78. Cottrell RC. Introduction: nutritional aspects of palm oil.1991 April 1;53:989S-1009S
  79. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels. 2016
  80. IOM (Institute of Medicine). Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Food and Nutrition Board. 2001:797.
  81. Vitamins and minerals – Vitamin A [Internet]. 2020 [cited 5 September 2020]. Available from:
  82. Nieman C, Obbink HK. The biochemistry and pathology of hypervitaminosis A. InVitamins & Hormones 1954 Jan 1 (Vol. 12, pp. 69-99). Academic Press. 
  83. Rodahl K. Toxicity of polar bear liver. Nature. 1949 Sep;164(4169):530-1.
  84. Rodahl K, Moore T. The vitamin A content and toxicity of bear and seal liver. Biochemical journal. 1943 Jul;37(2):166-8.
  85. Bendich A. The safety of β‐carotene. Nutrition and cancer. 1988 Jan 1;11(4):207-14.
  86. Furman KI. Acute hypervitaminosis A in an adult. The American journal of clinical nutrition. 1973 Jun 1;26(6):575-7.
  87. Di Benedetto RJ. Chronic hypervitaminosis A in an adult. JAMA. 1967 Aug 28;201(9):700-2.
  88. Binkley N, Krueger D. Hypervitaminosis A, and bone. Nutrition reviews. 2000 May 1;58(5):138-44.
  89. Robens JF. Teratogenic effects of hypervitaminosis A in the hamster and the guinea pig. Toxicology and Applied Pharmacology. 1970 Jan 1;16(1):88-99.
  90. Geelen JA, Peters PW. Hypervitaminosis A-induced teratogenesis. CRC Critical reviews in toxicology. 1979 Jan 1;6(4):351-75.
  91. Almohanna HM, Ahmed AA, Tsatalis JP, Tosti A. The role of vitamins and minerals in hair loss: a review. Dermatology and therapy. 2019 Mar 1;9(1):51-70.
  92. Shmunes E. Hypervitaminosis A in a patient with alopecia receiving renal dialysis. Archives of dermatology. 1979 Jul 1;115(7):882-3.
  93. Rayner RJ, Tyrrell JC, Hiller EJ, Marenah C, Neugebauer MA, Vernon SA, Brimlow G. Night blindness and conjunctival xerosis caused by vitamin A deficiency in patients with cystic fibrosis
  94. Sommer A, Sugana T. Corneal xerophthalmia and keratomalacia. Archives of Ophthalmology. 1982 Mar 1;100(3):404-11.. Archives of disease in childhood. 1989 Aug 1;64(8):1151-6.
  95. Lee WB, Hamilton SM, Harris JP, Schwab IR. Ocular complications of hypovitaminosis A after bariatric surgery. Ophthalmology. 2005 Jun 1;112(6):1031-4.
  96. Loewenthal LJ. A new cutaneous manifestation in the syndrome of vitamin A deficiency. Archives of Dermatology and Syphilology. 1933 Nov 1;28(5):700-8.
  97. Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005 Mar 1;90(2):F103-8.
  98. Shils ME, Shike M, editors. Modern nutrition in health and disease. Lippincott Williams & Wilkins; 2006.
  99. Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005 Mar 1;90(2):F103-8.
  100. Van Den Broek N, Dou L, Othman M, Neilson JP, Gates S, Guelmezoglu AM. Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database of Systematic Reviews. 2010(11).
  101. Parker GL, Smith LK, Baxendale IR. Development of the industrial synthesis of vitamin A. Tetrahedron. 2016 Mar 31;72(13):1645-52.
  102. Isler O. History and industrial application of carotenoids and vitamin A (1). InCarotenoids 5 1979 Jan 1 (pp. 447-462). Pergamon.
  103. Sorg O, Kuenzli S, Kaya G, Saurat JH. Proposed mechanisms of action for retinoid derivatives in the treatment of skin aging. Journal of cosmetic dermatology. 2005 Dec;4(4):237-44.
  104. Riahi RR, Bush AE, Cohen PR. Topical retinoids: therapeutic mechanisms in the treatment of photodamaged skin. American journal of clinical dermatology. 2016 Jun 1;17(3):265-76.
  105. Wolverton SE. Comprehensive Dermatologic Drug Therapy: Expert Consult-Online and Print. Elsevier Health Sciences; 2012 Nov 16.
  106. Gericke J, Ittensohn J, Mihály J, Álvarez S, Álvarez R, Töröcsik D, de Lera ÁR, Rühl R. Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin. PloS one. 2013 Apr 24;8(4):e62643.
  107. Griffiths CE. The role of retinoids in the prevention and repair of aged and photoaged skin. Clinical and experimental dermatology. 2001 Oct;26(7):613-8.
  108. Darlenski R, Surber C, Fluhr JW. Topical retinoids in the management of photodamaged skin: from theory to evidence‐based practical approach. British Journal of Dermatology. 2010 Dec;163(6):1157-65.
  109. Prockop DJ, Kivirikko KI, Tuderman L, Guzman NA. The biosynthesis of collagen and its disorders. New England Journal of Medicine. 1979 Jul 12;301(2):77-85.
  110. Angeles AM. Enhanced collagen gene expression in fibroblast cultures treated with all-trans-retinoic acid. Evidence for up-regulation of the α2 (I) promoter activity. J Invest Dermatol. 1990;84:504.
  111. Clark SD, Kobayashi DK, Welgus HG. Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. The Journal of clinical investigation. 1987 Nov 1;80(5):1280-8.
  112. Yaar M, Eller MS, Gilchrest BA. Fifty years of skin aging. InJournal of Investigative Dermatology Symposium Proceedings 2002 Dec 1 (Vol. 7, No. 1, pp. 51-58). Elsevier.
  113. Quan T, Fisher GJ. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontology. 2015;61(5):427-34.
  114. Shao Y, He T, Fisher GJ, Voorhees JJ, Quan T. Molecular basis of retinol anti‐ageing properties in naturally aged human skin in vivo. International journal of cosmetic science. 2017 Feb;39(1):56-65.
  115. Quan T, Shao Y, He T, Voorhees JJ, Fisher GJ. Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin. Journal of Investigative Dermatology. 2010 Feb 1;130(2):415-24.
  116. Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996 Jan;379(6563):335-9.
  117. Sorg O, Antille C, Kaya G, Saurat JH. Retinoids in cosmeceuticals. Dermatologic Therapy. 2006 Sep;19(5):289-96.
  118. Stratigos AJ, Katsambas AD. The role of topical retinoids in the treatment of photoaging. Drugs. 2005 Jun 1;65(8):1061-72.
  119. Costin GE, Hearing VJ. Human skin pigmentation: melanocytes modulate skin color in response to stress. The FASEB journal. 2007 Apr;21(4):976-94.
  120. Bellemere G, Stamatas GN, Bruere V, Bertin C, Issachar N, Oddos T. Antiaging action of retinol: from molecular to clinical. Skin pharmacology and physiology. 2009;22(4):200-9.
  121. Chung JH, Eun HC. Angiogenesis in skin aging and photoaging. The Journal of dermatology. 2007 Sep;34(9):593-600.
  122. Quan T, Wang F, Shao Y, Rittié L, Xia W, Orringer JS, Voorhees JJ, Fisher GJ. Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. Journal of Investigative Dermatology. 2013 Mar 1;133(3):658-67.
  123. Aldag C, Teixeira DN, Leventhal PS. Skin rejuvenation using cosmetic products containing growth factors, cytokines, and matrikines: a review of the literature. Clinical, cosmetic and investigational dermatology. 2016;9:411.
  124. Rossetti D, Kielmanowicz MG, Vigodman S, Hu YP, Chen N, Nkengne A, Oddos T, Fischer D, Seiberg M, Lin CB. A novel anti‐ageing mechanism for retinol: induction of dermal elastin synthesis and elastin fibre formation. International journal of cosmetic science. 2011 Feb;33(1):62-9.
  125. Zouboulis CC, Makrantonaki E. Clinical aspects and molecular diagnostics of skin aging. Clinics in dermatology. 2011 Jan 1;29(1):3-14.
  126. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris. American journal of clinical dermatology. 2008 Dec 1;9(6):369-81.
  127. Weinstein GD, Krueger GG, Lowe NJ, Duvic M, Friedman DJ, Jegasothy BV, Jorizzo JL, Shmunes E, Tschen EH, Lew-Kaya DA, Lue JC. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. Journal of the American Academy of Dermatology. 1997 Jul 1;37(1):85-92.
  128. Bollag W, Ott F. Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents and actions. 1970 Aug 1;1(4):172-5.
  129. Antille C, Tran C, Sorg O, Carraux P, Didierjean L, Saurat JH. Vitamin A exerts a photoprotective action in skin by absorbing ultraviolet B radiation. Journal of Investigative Dermatology. 2003 Nov 1;121(5):1163-7.
  130. Veraldi S, Brena M, Barbareschi M. Allergic contact dermatitis caused by topical antiacne drugs. Expert review of clinical pharmacology. 2015 Jul 4;8(4):377-81.
  131. Retinoids, topical – American Osteopathic College of Dermatology (AOCD) [Internet]. 2020 [cited 15 September 2020]. Available from:
  132. Kang S, Duell EA, Fisher GJ, Datta SC, Wang ZQ, Reddy AP, Tavakkol A, Jong YY, Griffiths CE, Elder JT, Voorhees JJ. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. Journal of Investigative Dermatology. 1995 Oct 1;105(4):549-56.
  133. Schultink W. Use of under-five mortality rate as an indicator for vitamin A deficiency in a population. The Journal of nutrition. 2002 Sep 1;132(9):2881S-3S.
  134. Moon TE, Levine N, Cartmel B, Bangert JL, Rodney S, Dong Q, Peng YM, Alberts DS. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiology and Prevention Biomarkers. 1997 Nov 1;6(11):949-56.
  135. Abar L, Vieira AR, Aune D, Stevens C, Vingeliene S, Navarro Rosenblatt DA, Chan D, Greenwood DC, Norat T. Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies. Cancer medicine. 2016 Aug;5(8):2069-83. 
  136. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens Jr FL, Valanis B, Williams Jr JH, Barnhart S. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. JNCI: Journal of the National Cancer Institute. 1996 Nov 6;88(21):1550-9.
  137. Omenn GS. Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annual review of public health. 1998 May;19(1):73-99.
  138. Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D. Associations between α-tocopherol, β-carotene, and retinol and prostate cancer survival. Cancer research. 2009 May 1;69(9):3833-41.
  139. Neuhouser ML, Barnett MJ, Kristal AR, Ambrosone CB, King IB, Thornquist M, Goodman GG. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiology and Prevention Biomarkers. 2009 Aug 1;18(8):2202-6.
  140. Walsh JA, Warren KS. Selective primary health care: an interim strategy for disease control in developing countries. Social Science & Medicine. Part C: Medical Economics. 1980 Jun 1;14(2):145-63.
  141. Frieden TR, Sowell AL, Henning KJ, Huff DL, Gunn RA. Vitamin A levels and severity of measles: New York City. American Journal of Diseases of Children. 1992 Feb 1;146(2):182-6.
  142. WHO., WHO/UNICEF/IVACG Task Force, International Vitamin A Consultative Group, UNICEF., World Health Organization. Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia. World Health Organization; 1997.
  143. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Survey of ophthalmology. 2003 May 1;48(3):257-93.
  144. Beatty S, Koh HH, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Survey of ophthalmology. 2000 Sep 1;45(2):115-34.

145.  Chew EY, Clemons TE, SanGiovanni JP, Danis R, Ferris FL, Elman M, Antoszyk A, Ruby A, Orth D, Bressler S, Fish G. Lutein+ zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA-Journal of the American Medical Association. 2013 May 15;309(19):2005-15.

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