Vitamin A

Vitamin A is a fat-soluble vitamin, a category that also includes vitamins D, E and K. The vitamin encompasses several chemically related naturally occurring compounds or metabolites, i.e., vitamers, that all contain a β-ionone ring. :retinal + NADH + H+ retinol + NAD+ :retinol + NAD+ retinal + NADH + H+ Retinal (also known as retinaldehyde) can be irreversibly converted to all-trans-retinoic acid by the action of retinal dehydrogenase :retinal + NAD+ + H2O → retinoic acid + NADH + H+ Retinoic acid is actively transported into the cell nucleus by CRABp2 where it regulates thousands of genes by binding directly to gene targets via retinoic acid receptors. ==Absorption, metabolism and excretion==

Retinyl esters from animal-sourced foods (or synthesized for dietary supplements for humans and domesticated animals) are acted upon by retinyl ester hydrolases in the lumen of the small intestine to release free retinol. Retinol enters enterocytes by passive diffusion. Absorption efficiency is in the range of 70 to 90%. Humans are at risk for acute or chronic vitamin A toxicity because there are no mechanisms to suppress absorption or excrete the excess in urine. The capacity to store retinol in the liver means that well-nourished humans can go months on a vitamin A deficient diet without manifesting signs and symptoms of deficiency. Two liver cell types are responsible for storage and release: hepatocytes and hepatic stellate cells (HSCs). Hepatocytes take up the lipid-rich chylomicrons, bind retinol to retinol-binding protein 4 (RBP4), and transfer the retinol-RBP4 to HSCs for storage in lipid droplets as retinyl esters. Mobilization reverses the process: retinyl ester hydrolase releases free retinol which is transferred to hepatocytes, bound to RBP4, and put into blood circulation. Other than either after a meal or when consumption of large amounts exceeds liver storage capacity, more than 95% of retinol in circulation is bound to RBP4. As noted, in humans, retinol circulates bound to RBP4. Carnivores maintain R-RBP4 within a tight range while also having retinyl esters in circulation. Bound retinol is delivered to cells while the esters are excreted in the urine. ==Metabolic functions==

Other than for vision, the metabolic functions of vitamin A are mediated by all-trans-retinoic acid (RA). The formation of RA from retinal is irreversible. To prevent accumulation of RA it is oxidized and eliminated fairly quickly, i.e., has a short half-life. Three cytochromes catalyze the oxidation of retinoic acid. The genes for Cyp26A1, Cyp26B1 and Cyp26C1 are induced by high levels of RA, providing a self-regulating feedback loop. Vision and eye health Vitamin A status involves eye health via two separate functions. Retinal is an essential factor in rod cells and cone cells in the retina responding to light exposure by sending nerve signals to the brain. An early sign of vitamin A deficiency is night blindness. Xerophthalmia and childhood blindness Xerophthalmia, caused by a severe vitamin A deficiency, is described by pathologic dryness of the conjunctival epithelium and cornea. The conjunctiva becomes dry, thick, and wrinkled. Indicative is the appearance of Bitot's spots, which are clumps of keratin debris that build up inside the conjunctiva. If untreated, xerophthalmia can lead to dry eye syndrome, corneal ulceration and ultimately to blindness as a result of cornea and retina damage. Although xerophthalmia is an eye-related issue, prevention (and reversal) are functions of retinoic acid having been synthesized from retinal rather than the 11-cis-retinal to rhodopsin cycle. Estimates are that each year there are 350,000 cases of childhood blindness due to vitamin A deficiency. The causes are vitamin A deficiency during pregnancy, followed by low transfer of vitamin A during lactation and infant/child diets low in vitamin A or β-carotene. Upon binding retinoic acid, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery. This response upregulates or downregulates the expression of target genes, including the genes that encode for the receptors themselves. including congenital vascular and cardiovascular defects. Of note, fetal alcohol spectrum disorder encompasses congenital anomalies, including craniofacial, auditory, and ocular defects, neurobehavioral anomalies and mental disabilities caused by maternal consumption of alcohol during pregnancy. It is proposed that in the embryo there is competition between acetaldehyde, an ethanol metabolite, and retinaldehyde (retinal) for aldehyde dehydrogenase activity, resulting in a retinoic acid deficiency, and attributing the congenital birth defects to the loss of RA activated gene activation. In support of this theory, ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol or retinal. Immune functions Vitamin A deficiency has been linked to compromised resistance to infectious diseases. In countries where early childhood vitamin A deficiency is common, vitamin A supplementation public health programs initiated in the 1980s were shown to reduce the incidence of diarrhea and measles, and all-cause mortality. Vitamin A deficiency also increases the risk of immune system over-reaction, leading to chronic inflammation in the intestinal system, stronger allergic reactions and autoimmune diseases. Lymphocytes include natural killer cells, which function in innate immunity, T cells for adaptive cellular immunity and B cells for antibody-driven adaptive humoral immunity. Monocytes differentiate into macrophages and dendritic cells. Some lymphocytes migrate to the thymus where they differentiate into several types of T cells, in some instances referred to as "killer" or "helper" T cells and further differentiate after leaving the thymus. Each subtype has functions driven by the types of cytokines secreted and organs to which the cells preferentially migrate, also described as trafficking or homing. Retinoic acid (RA) triggers receptors in bone marrow, resulting in generation of new white blood cells. RA regulates proliferation and differentiation of white blood cells, the directed movement of T cells to the intestinal system, and to the up- and down-regulation of lymphocyte function. If RA is adequate, T helper cell subtype Th1 is suppressed and subtypes Th2, Th17 and iTreg (for regulatory) are induced. Dendritic cells located in intestinal tissue have enzymes that convert retinal to all-trans-retinoic acid, to be taken up by retinoic acid receptors on lymphocytes. The process triggers gene expression that leads to T cell types Th2, Th17 and iTreg moving to and taking up residence in mesenteric lymph nodes and Peyer's patches, respectively outside and on the inner wall of the small intestine. A meta-analysis of clinical trials conducted in countries where VAD is prevalent concluded that when children were supplemented with vitamin A, there was a 50% reduction in incidence of contracting measles. Vitamin A supplementation is not thought to reduce the risk of death from measles. Multiple children hospitalized for measles at Covenant Children's Hospital in Lubbock also showed signs of liver damage, a symptom of vitamin A toxicity. Skin Deficiencies in vitamin A have been linked to an increased susceptibility to skin infection and inflammation. Vitamin A appears to modulate the innate immune response and maintains homeostasis of epithelial tissues and mucosa through its metabolite, retinoic acid (RA). As part of the innate immune system, toll-like receptors in skin cells respond to pathogens and cell damage by inducing a pro-inflammatory immune response which includes increased RA production. The epithelium of the skin encounters bacteria, fungi and viruses. Keratinocytes of the epidermal layer of the skin produce and secrete antimicrobial peptides (AMPs). Production of AMPs resistin and cathelicidin, are promoted by RA. ==Units of measurement==

As some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. The situation can be confusing because the accepted equivalences have changed over time. For many years, a system of equivalencies in which an international unit (IU) was equal to 0.3 μg of retinol (~1 nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used. This relationship was alternatively expressed by the retinol equivalent (RE): one RE corresponded to 1 μg retinol, to 2 μg β-carotene dissolved in oil, to 6 μg β-carotene in foods, and to 12 μg of either α-carotene, γ-carotene, or β-cryptoxanthin in food. Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" β-carotene, or 24 μg of the three other dietary provitamin-A carotenoids. Animal models have shown that at the enterocyte cell wall, β-carotene is taken up by the membrane transporter protein scavenger receptor class B, type 1 (SCARB1). Absorbed β-carotene is converted to retinal and then retinol. The first step of the conversion process consists of one molecule of β-carotene cleaved by the enzyme β-carotene-15, 15'-monooxygenase, which in humans and other mammalian species is encoded by the BCM01 gene, into two molecules of retinal. When plasma retinol is in the normal range, gene expression for SCARB1 and BC01 are suppressed, creating a feedback loop that suppresses β-carotene absorption and conversion. Absorption suppression is not complete, as receptor 36 is not downregulated. ==Dietary recommendations==

The US National Academy of Medicine updated Dietary Reference Intakes (DRIs) in 2001 for vitamin A, which included Recommended Dietary Allowances (RDAs). For infants up to 12 months, there was not sufficient information to establish an RDA, so Adequate Intake (AI) is shown instead. As for safety, tolerable upper intake levels (ULs) were also established. For ULs, carotenoids are not added when calculating total vitamin A intake for safety assessments. The EFSA reviewed the same safety question as the United States, and set ULs at 800 for ages 1–3, 1100 for ages 4–6, 1500 for ages 7–10, 2000 for ages 11–14, 2600 for ages 15–17 and 3000 μg/day for ages 18 and older for preformed vitamin A, i.e., not including dietary contributions from carotenoids. Safety Vitamin A toxicity (hypervitaminosis A) occurs when too much vitamin A accumulates in the body. It comes from consumption of preformed vitamin A but not of carotenoids, as conversion of the latter to retinol is suppressed by the presence of adequate retinol. Retinol safety There are historical reports of acute hypervitaminosis from Arctic explorers consuming bearded seal or polar bear liver, both very rich sources of stored retinol, and there are also case reports of acute hypervitaminosis from consuming fish liver, but otherwise there is no risk from consuming too much via commonly consumed foods. Only consumption of retinol-containing dietary supplements can result in acute or chronic toxicity. Chronic toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU/day for several months. The European Food Safety Authority, acting for the European Union, also decided not to set a UL for β-carotene. Consumption of greater than 30 mg/day for a prolonged period has been confirmed as leading to carotenemia. U.S. labeling For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin A labeling purposes, 100% of the Daily Value was set at 5,000 IU, but it was revised to 900 μg RAE on 27 May 2016. A table of the old and new adult daily values is provided at Reference Daily Intake. ==Sources==

Primary causes Vitamin A deficiency is common in developing countries, especially in Sub-Saharan Africa and Southeast Asia. Deficiency can occur at any age, but is most common in pre-school-age children and pregnant women, the latter due to a need to transfer retinol to the fetus. The causes are low intake of retinol-containing, animal-sourced foods and low intake of carotene-containing, plant-sourced foods. Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world, possibly leading to the deaths of 670,000 children under five annually. Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency. Secondary causes There are causes for deficiency other than low dietary intake of vitamin A as retinol or carotenes. Adequate dietary protein and caloric energy are needed for a normal rate of synthesis of RBP, without which, retinol cannot be mobilized to leave the liver. Systemic infections can cause transient decreases in RBP synthesis even if protein-calorie malnutrition is absent. Chronic alcohol consumption reduces liver vitamin A storage. Vitamin A appears to be involved in the pathogenesis of anemia by diverse biological mechanisms, such as the enhancement of growth and differentiation of erythrocyte progenitor cells, potentiation of immunity to infection, and mobilization of iron stores from tissues. ==Animal requirements==

All vertebrate and chordate species require vitamin A, also commercially raised chickens and turkeys. Herbivore species such as horses, cattle and sheep can get sufficient β-carotene from green pasture to be healthy, but the content in pasture grass dry due to drought and long-stored hay can be too low, leading to vitamin A deficiency. Invertebrates cannot synthesize carotenoids or retinol, and thus must accrue these essential nutrients from consumption of algae, plants or animals. ==Medical uses==

In 2022, vitamin A was the 346th most commonly prescribed medication in the United States, with more than 50,000 prescriptions. Preventing and treating vitamin A deficiency Recognition of its prevalence and consequences has led to governments and non-government organizations promoting vitamin A fortification of foods A Cochrane review reported that vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children ages six month to five years of age. All-cause mortality was reduced by 14%, and incidence of diarrhea by 12%. Tretinoin is usually applied as a skin cream to the face after cleansing to remove make-up and skin oils, while isotretinoin is taken orally. Tretinoin and isotretinoin act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation. The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation. These drugs, when applied topically, are US-designated Pregnancy Category C (animal reproduction studies have shown an adverse effect on the fetus), and should not be used by pregnant women or women who are anticipating becoming pregnant. Trifarotene is a prescription retinoid for the topical treatment acne vulgaris. Non-prescription topical products that have health claims for reducing facial acne, combating skin dark spots and reducing wrinkles and lines associated with aging often contain retinyl palmitate. The hypothesis is that this is absorbed and de-esterified to free retinol, then converted to retinaldehyde and further metabolized to all-trans-retinoic acid, whence it will have the same effects as prescription products with fewer side effects. There is some ex vivo evidence with human skin that esterified retinol is absorbed and then converted to retinol. In addition to esterified retinol, some of these products contain hydroxypinacolone retinoate, identified as esterified 9-cis-retinoic acid. Oral isotretinoin Oral isotretinoin (retinoic acid isomer) is recommended for treating treatment resistant acne, acne that can lead to scarring, and acne that is associated with psychosocial distress. It is approved by the FDA for treating severe acne vulgaris that is resistant to other treatment options. Rosacea was reported as responding favorably to doses lower than used for acne. Isotretinoin in combination with ultraviolet light was shown affective for treating psoriasis. Isotretinoin in combination with injected interferon-alpha showed some potential for treating genital warts. Isotretinoin in combination with topical fluorouracil or injected interferon-alpha showed some potential for treating precancerous skin lesions and skin cancer. The anti-inflammatory effects of vitamin A also contribute to repairing mucosal cells that can be damaged by an infection. For these reasons, there have been quite a few studies looking at the potential role that Vitamin A supplementation may play in improving an immune response or to helping the body fight off an infection. The evidence supporting vitamin A supplementation for children under the age of 7 years to prevent upper respiratory tract infections is weak, and the weak evidence from low-quality clinical trials does not support vitamin A as being effective or having a benefit. More research is needed to consider different doses, the ages and populations of people who may potentially benefit, and the length of treatment. ==Synthesis==

Biosynthesis Carotenoid synthesis takes place in plants, certain fungi, and bacteria. Structurally carotenes are tetraterpenes, meaning that they are synthesized biochemically from four 10-carbon terpene units, which in turn were formed from eight 5-carbon isoprene units. Intermediate steps are the creation of a 40-carbon phytoene molecule, conversion to lycopene via desaturation, and then creation of ionone rings at both ends of the molecule. β-carotene has a β-ionone ring at both ends, meaning that the molecule can be divided symmetrically to yield two retinol molecules. α-Carotene has a β-ionone ring at one end and an Ɛ-ionone ring at the other, so it has half the retinol conversion capacity. In most animal species, retinol is synthesized from the breakdown of the plant-formed provitamin, β-carotene. First, the enzyme beta-carotene 15,15'-dioxygenase (BCO-1) cleaves β-carotene at the central double bond, creating an epoxide. This epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. The cleavage occurs when these alcohols are oxidized to the aldehydes using NAD+. The resultant retinal is then quickly reduced to retinol by the enzyme retinol dehydrogenase. Chemical synthesis uses either a method developed by BASF or a Grignard reaction utilized by Hoffman-La Roche. The world market for synthetic retinol is primarily for animal feed, leaving approximately 13% for a combination of food, prescription medication and dietary supplement use. Pure retinol is extremely sensitive to oxidization and is prepared and transported at low temperatures and oxygen-free atmospheres. When prepared as a dietary supplement or food additive, retinol is stabilized as the ester derivatives retinyl acetate or retinyl palmitate. Prior to 1999, three companies, Roche, BASF and Rhone-Poulenc controlled 96% of global vitamin A sales. In 2001, the European Commission imposed total fines of 855.22 million euros on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989. Roche sold its vitamin division to DSM in 2003. DSM and BASF have the major share of industrial production. ==Research==

Brain Animal research (on mice), which is pre-clinical, also found Retinoid acid, the bioactive metabolite of vitamin A, to have an effect on brain areas responsible for memory and learning. Cancer Meta-analyses of intervention and observational trials for various types of cancer report mixed results. Supplementation with β-carotene did not appear to decrease the risk of cancer overall, nor specific cancers including: pancreatic, colorectal, prostate, breast, melanoma, or skin cancer generally. High-dose β-carotene supplementation unexpectedly resulted in a higher incidence of lung cancer and of total mortality in people who were cigarette smokers. risk of liver cancer, risk of bladder cancer or risk of colorectal cancer, although the last review did report lower risk for higher β-carotene consumption. gastric cancer, ovarian cancer, pancreatic cancer, lung cancer, melanoma, and cervical cancer. For lung cancer, an inverse association was also seen for β-carotene intake, separate from the retinol results. Fetal alcohol spectrum disorder Fetal alcohol spectrum disorder (FASD), formerly referred to as fetal alcohol syndrome, presents as craniofacial malformations, neurobehavioral disorders and mental disabilities, all attributed to exposing human embryos to alcohol during fetal development. Ethanol is a known teratogen, i.e., causes birth defects. Ethanol is metabolized by alcohol dehydrogenase enzymes into acetaldehyde. The subsequent oxidation of acetaldehyde into acetate is performed by aldehyde dehydrogenase enzymes. Given that retinoic acid (RA) regulates numerous embryonic and differentiation processes, one of the proposed mechanisms for the teratogenic effects of ethanol is a competition for the enzymes required for the biosynthesis of RA from vitamin A. Animal research demonstrates that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for aldehyde dehydrogenase activity. In this model, acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Thus, animal research supports the reduction of retinoic acid activity as an etiological trigger in the induction of FASD. Malaria Malaria and vitamin A deficiency are both common among young children in sub-Saharan Africa. Vitamin A supplementation to children in regions where vitamin A deficiency is common has repeatedly been shown to reduce overall mortality rates, especially from measles and diarrhea. The question was raised as to whether malaria causes vitamin A deficiency, or vitamin A deficiency contributes to the severity of malaria, or both. Researchers proposed several mechanisms by which malaria (and other infections) could contribute to vitamin A deficiency, including a fever-induced reduction in synthesis of retinal-binding protein (RBP) responsible for transporting retinol from liver to plasma and tissues, but reported finding no evidence for a transient depression or restoration of plasma RBP or retinol after a malarial infection was eliminated. ==History==

In 1912, Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929. By 1913, one of these substances was independently discovered by Elmer McCollum and Marguerite Davis at the University of Wisconsin–Madison, and Lafayette Mendel and Thomas Burr Osborne at Yale University. McCollum and Davis ultimately received credit because they submitted their paper three weeks before Mendel and Osborne. Both papers appeared in the same issue of the Journal of Biological Chemistry in 1913. The "accessory factors" were termed "fat soluble" in 1918, and later "vitamin A" in 1920. In 1919, Harry Steenbock (University of Wisconsin–Madison) proposed a relationship between yellow plant pigments (β-carotene) and vitamin A. In 1931, Swiss chemist Paul Karrer described the chemical structure of vitamin A. During World War II, German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-board Airborne Intercept Radar system secret from Germany, the British Ministry of Information told newspapers an unproven claim that the nighttime defensive success of Royal Air Force pilots was due to a high dietary intake of carrots rich in β-carotene, successfully convincing many people. In 1967, George Wald shared the Nobel Prize in Physiology and Medicine for his work on chemical visual processes in the eye. Wald had demonstrated in 1935 that photoreceptor cells in the eye contain rhodopsin, a chromophore composed of the protein opsin and 11-cis-retinal. When struck by light, 11-cis-retinal undergoes photoisomerization to all-trans-retinal and via signal transduction cascade send a nerve signal to the brain. The all-trans-retinal is reduced to all-trans-retinol and travels back to the retinal pigment epithelium to be recycled to 11-cis-retinal and reconjugated to opsin. Wald's work was the culmination of nearly 60 years of research. In 1877, Franz Christian Boll identified a light-sensitive pigment in the outer segments of rod cells of the retina that faded/bleached when exposed to light, but was restored after light exposure ceased. He suggested that this substance, by a photochemical process, conveyed the impression of light to the brain. == References ==