Vitamin A is the name given to natural and synthetic compounds with chemically similar structure but different biological activity. A unified nomenclature was proposed by the IUPAC-IUB Joint Commission on Biochemical Nomenclature based on the chemical similarities (1982). According to this, vitamin A is a generic term for compounds that are not carotenoids and have the biological activity of retinol, the vitamin A alcohol. This definition of the term is problematic with regard to orthomolecular action, since not all vitamin A derivatives (derivatives) have full vitamin A activity. For this reason, a classification according to biological-medical aspects is recommended. According to it, the name vitamin A applies to compounds that have all the effects of the vitamin. These compounds include retinol and retinyl esters (fatty acid esters of retinol), such as retinyl acetate, palmitate and propionate, which are metabolizable to retinal and retinoic acid, as well as carotenoids with provitamin A activity, such as beta-carotene. Retinoids – natural and synthetic retinoic acid derivatives – on the other hand, do not exhibit full vitamin A activity because they cannot be metabolized to the parent substance retinol. They have no effect on spermatogenesis (formation of sperm) or on the visual cycle. The biological effect of vitamin A is expressed in International Units (IU) and retinol equivalents (RE), respectively:
- 1 IU of vitamin A is equivalent to 0.3 µg of retinol
- 1 RE corresponds to 1 µg retinol 6 µg beta-carotene 12 µg other carotenoids with provitamin A effect.
However, it has been shown that the bioavailability of alimentary (dietary) vitamin A-active carotenoids and their bioconversion (enzymatic conversion) to retinol have previously been significantly overestimated. According to recent findings, provitamin A carotenoids exhibit only 50% of the previously assumed retinol activity. Thus, the conversion factor 6, which was used to calculate the vitamin A activity of beta-carotene, has now been corrected upward. It is now assumed that 1 µg of retinol.
- 12 µg beta-carotene, respectively.
- 24 µg of other carotenoids with provitamin A effect correspond to.
Structural feature of vitamin A is the polyunsaturated polyene structure, consisting of four isoprenoid units with conjugated double bonds (a chemical structural feature that alternates a single bond and a double bond). The isoprenoid side chain is attached to a beta ionone ring. At the end of the acyclic part there is a functional group that can be modified in the organism. Thus, esterification (equilibrium reaction in which an alcohol reacts with an acid) of retinol with fatty acids leads to retinyl ester, and oxidation of retinol reversibly (reversible) to retinal (vitamin A aldehyde) and irreversibly (irreversible) to retinoic acid, respectively. Both the beta-ionone ring and the isoprenoid chain are molecular prerequisites for vitamin A efficacy. Changes in the ring and a side chain with < 15 C atoms and < 2 methyl groups, respectively, lead to reductions in activity. Thus, carotenoids with an oxygen-bearing ring or without a ring structure have no vitamin A activity. Conversion of the all-trans retinol to its cis isomers results in a structural change and is also associated with lower biological activity.
Synthesis
Vitamin A is found exclusively in animal and human organisms. In this context, it is largely derived from the breakdown of carotenoids that humans and animals, respectively, ingest with food. The conversion of provitamins A takes place in the intestine and in the liver. Decentralized cleavage of beta-carotene by the enzyme 15,15′-dioxygenase – carotenase – of enterocytes (cells of the small intestinal epithelium) results in 8′-, 10′- or 12′-beta-apocarotene, depending on the site of degradation (breakdown) of the molecule, which is converted to retinal by further degradation or chain shortening, respectively. Upon central cleavage of beta-carotene by liver alcohol dehydrogenase, two molecules of retinal are regenerated (formed). Retinal can subsequently be either reduced to the biologically active retinol – reversible process – or oxidized to retinoic acid – irreversible conversion. However, oxidation of retinal to retinoic acid occurs to a much lesser extent.The conversion of beta-carotene and other provitamins A to retinol differs in different species and depends on dietary characteristics affecting intestinal absorption and on individual vitamin A supply. Approximately equivalent in effect to 1 µg of all-trans-retinol are:
- 2 µg beta-carotene in milk; 4 µg beta-carotene in fats.
- 8 µg beta-carotene in homogenized carrots or cooked vegetables prepared with fat.
- 12 µg beta-carotene in cooked, strained carrots.
Absorption
Like all fat-soluble vitamins, vitamin A is absorbed (taken up) in the upper small intestine during fat digestion, i.e. the presence of dietary fats as transporters of lipophilic (fat-soluble) molecules, bile acids to solubilize (increase solubility) and form micelles (form transport beads that make fat-soluble substances transportable in aqueous solution), and esterases (digestive enzymes) to cleave retinyl esters is necessary for optimal intestinal absorption (absorption through the intestine). Vitamin A is absorbed either in the form of its provitamin – usually beta-carotene – from plant foods or in the form of its fatty acid esters – usually retinyl palmitate – from animal products. The retinyl esters are hydrolytically cleaved (by reaction with water) in the intestinal lumen by cholesterylesterase (digestive enzyme). The retinol released in this process reaches the brush border membrane of the mucosa cells (cells of the intestinal mucosa) as a component of the mixed micelles and is internalized (absorbed internally) [1-4, 6, 9, 10]. The absorption rate of retinol ranges from 70-90%, depending on the literature, and is highly dependent on the type and amount of fat supplied at the same time. While in the physiological (normal for metabolism) concentration range, the absorption of retinol occurs according to saturation kinetics in an energy-independent manner corresponding to carrier-mediated passive diffusion, pharmacological doses are absorbed by passive diffusion. In enterocytes (cells of the small intestinal epithelium), retinol is bound to cellular retinol-binding protein II (CRBPII) and esterified by the enzymes lecithin-retinol acyltransferase (LRAT) and acyl-CoA-retinol acyltransferase (ARAT) with fatty acids, primarily palmitic acid. This is followed by incorporation (uptake) of retinyl esters into chylomicrons (lipid-rich lipoproteins), which enter the peripheral circulation via the lymph and are degraded to chylomicron remnants (low-fat chylomicron remnants).
Transport and distribution in the body
During transport to the liver, retinyl esters may be taken up to a small extent by the enzyme lipoprotein lipase (LPL) into various tissues, for example, muscle, adipose tissue, and mammary gland. However, the majority of the esterified retinol molecules remain in the chylomicron remnants, which bind to specific receptors (binding sites) in the liver. This results in the uptake of retinyl esters into the liver and hydrolysis to retinol in the lysosomes (cell organelles) of parenchymal cells. In the cytoplasm of the parenchymal cells, retinol is bound to cellular retinol-binding protein (CRBP). The retinol bound to CRBP can, on the one hand, serve as short-term storage in the parenchymal cells, be functionally used or metabolized, and, on the other hand, be stored long-term as excess retinol by the perisinusoidal stellate cells (fat-storing stellate or Ito cells; 5-15% of liver cells) after esterification – mostly with palmitic acid – as retinyl esters. Retinyl esters of perisinusoidal stellate cells account for about 50-80% of the total body vitamin A pool and about 90% of the total liver concentration. The storage capacity of stellate cells is almost unlimited. Thus, even with chronically high intakes, these cells can hold many times the usual amount of storage. Healthy adults have an average concentration of retinyl esters of 100-300 µg and children of 20-100 µg per g of liver. The half-life of retinyl esters stored in the liver is 50-100 days, or less in chronic alcohol consumption [1-3, 6, 9]. To mobilize stored vitamin A, retinyl esters are cleaved by a specific retinyl ester hydrolase (an enzyme). The resulting retinol, initially bound to CRBP, is released to the intracellular (located inside the cell) apo-retinol-binding protein (apo-RBP), bound, and secreted (secreted) into the blood plasma as holo-RBP.Since the retinol-RBP complex would be rapidly lost in the glomerular filtrate of the kidney due to its low molecular weight, reversible binding of holo-RBP to transthyretin (TTR, thyroxine-binding prealbum) occurs in the blood. The retinol-RBP-TTR complex (1:1:1) travels to extrahepatic (outside the liver) tissues, such as the retina, testis, and lung, where retinol is taken up by cells in a receptor-mediated manner and bound intracellularly to CRBP for transport both within the cell and through blood/tissue barriers. While the extracellular remaining TTR is available for renewed transport processes in blood plasma, Apo-RBP is catabolized (degraded) by the kidney. In the metabolism of cells, conversions include the following:
- Reversible dehydrogenation (splitting off of hydrogen) of retinol – retinol ↔ retinal.
- Irreversible oxidation of retinal to retinoic acid – retinal → retinoic acid.
- Isomerizations (conversion of the molecule to another isomer) – trans ↔ cis – of retinol, retinal or retinoic acid.
- Esterification of retinol with fatty acids – retinol ↔ retinyl ester – to bridge a short-term supply deficit.
Retinoic acid – all-trans and 9-cis – interacts in target cells, bound to cellular retinoic acid-binding protein (CRABP), with nuclear retinoic acid receptors – RAR and RXR with subtypes – belonging to the steroid-thyroid (thyroid) hormone receptor family. RXR preferentially bind 9-cis-retinoic acid and form heterodimers (molecules composed of two different subunits) by contact with other receptors, such as all-trans-retinoic acid, triiodothyronine (T3; thyroid hormone), calcitriol (vitamin D), estrogen, or progesterone receptors. As transcription factors, the nuclear retinoic acid receptors influence gene expression by binding to specific DNA sequences. Thus, retinoic acid is an important regulator of cell and tissue growth and differentiation.
Excretion
Approximately 20% of orally supplied vitamin A is not absorbed and is eliminated via bile and feces or urine. To convert vitamin A into an excretable form, it undergoes biotransformation, as do all lipophilic (fat-soluble) substances. Biotransformation takes place in the liver and can be divided into two phases:
- In phase I, vitamin A is hydroxylated (insertion of an OH group) by the cytochrome P-450 system to increase solubility.
- In phase II, conjugation occurs with highly hydrophilic (water-soluble) substances – for this purpose, glucuronic acid is transferred to the previously inserted OH group of vitamin A with the help of glucuronyltransferase
Much of the metabolites have not yet been elucidated. However, it can be assumed that the excretion products are mainly glucuronidated and free retinoic acid and 4-ketoretic acid, respectively.
