Analysis of the current vitamin A terminology and dietary regulations from vitamin A1 to vitamin A5
Abstract
Abstract: Dietary recommendations on vitamin intake for human food fortification concerning vitamin A in various countries, larger economic zones and international organizations are mainly based on the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) “Codex Alimentarius standards”. The general vitamin A terminology is based on regulations of the International Union of Pure and Applied Chemistry (IUPAC) that are used to describe the involved derivatives. These regulations and terminology were set up in the middle of the last century. Starting with the decade of the 80ies in the 20th century a large improvement of molecular biological methodologies, background physiological mechanisms as well as analytical techniques contributed to a large diversification of this simply claimed vitamin A terminology. Unfortunately, the following terminology and governmental regulations for food fortification are imprecise and non-harmonized. In this article we tried to unravel this terminology for updating terminology, nutritional suggestions and governmental regulations for vitamin A, which are currently based on various uncertainties. According to the current regulations, the newly found vitamin A5/X can be included in the current vitamin A terminology as “vitamin A5” or alternatively or even in parallel as a new vitamin A-independent terminology as “vitamin X”. Based on the detailed knowledge of research from the early beginning of general vitamin A pathway identification towards detailed research of the last decades the commonly used and simplified term vitamin A with relevance for governmental recommendations on vitamin intake and food fortification advice was now more correctly sub-categorized to further vitamin A1, and A5 sub-categories with vitamin A1-alcohol as retinol, vitamin A2-alcohol as 3,4-didehydroretinol and vitamin A5-alcohol as 9-cis-13,14-dihydroretinol as their mainly relevant vitamin forms present in the human organism. Here we suggest and advise how the vitamin A terminology and further governmental regulations should be organized depending on a successful unraveling of the organization of the current vitamin A terminology.
References
1 . Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling. Nutr Res Rev. 2023;36(2):498–511.
2 Mechanistic aspects of carotenoid health benefits – where are we now? Nutr Res Rev. 2021;34(2):276–302.
3 From carotenoid intake to carotenoid blood and tissue concentrations – implications for dietary intake recommendations. Nutr Rev. 2021;79:544–73.
4 . Guidelines on Nutrient labelling CAC/GL 2-1985. WHO/FAO 2017.
5 . Proposed draft amendments to the international system for food additives (CX 36-1989). WHO/FAO 2019 2017, CX/FA 19/51/12.
6 . Scientific opinion on dietary reference values for vitamin A. EFSA J. 2015;13(3):4028.
7 . Statement on the safety of ß-carotene use in heavy smokers. EFSA Journal. 2012;10(12):2953.
8 . Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press: Washington, DC; 2001.
9 . Guidance & Regulation (Food and Dietary Supplements). 2021. https://www.fda.gov/food/guidance-regulation-food-and-dietary-supplements
10 . Retinoid signaling distinguishes a subpopulation of olfactory receptor neurons in the developing and adult mouse. J Comp Neurol. 1998;394:445–61.
11 . Nomenclature of retinoids. Recommondations. Eur J Biochem. 1982;129:1–5.
12 Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling. Nutrients. 2021;13(3):925.
13 . The Biochemical basis of vitamin A3 production in athopod vision. ACS Chem Biol. 2016;11(4):1049–57.
14 . 9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutr Rev. 2018;76:929–41.
15 . Studies in vitamin A. XXI. Retinene2 and vitamin A2. Biochem J. 1952;52:542–7.
16 . Isolation of pure vitamin A2. Science. 1948;108:417–9.
17 . Vitamin and mineral requirements in human nutrition; report of a joint FAO/WHO expert consultation. WHO/FAO of the UN: Bankok, Thailand:; 1998.
18 . Retinol and retinyl esters: biochemistry and physiology. J Lipid Res. 2013;54:1731–43.
19 B-Carotene in the Human body – Metabolic acitivation pathways – from Digestion to Tissue Distribution. Proc Nutr Soc. 2019;78(1):68–87.
20 From carotenoid intake to carotenoid blood and tissue concentrations – implications for dietary intake recommendations. Nutr Rev. 2021;79(5):544–73.
21 , Effects of dietary retinoids and carotenoids on immune development. Proc Nutr Soc. 2007;66:458–69.
22 . Vitamin A [Internet]. EEUU: StatPearls; 2020.
23 . HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues. Anal Biochem. 2008;378:71–9.
24 . Simultaneous quantification of retinol, retinal, and retinoic acid isomers by high-performance liquid chromatography with a simple gradiation. J Chromatogr B Biomed Sci Appl. 2001;757:365–8.
25 . High-performance liquid chromatographic analysis of retinal and retinol isomers. J Chromatogr A. 1996;721:247–59.
26 . Hydrolysis of cis and trans isomers of retinyl palmitate by retinyl ester hydrolase of pig liver. Arch Biochem Biophys. 1988;260:705–11.
27 . Separation of geometric isomers of retinyl ester, retinal and retinol, pertaining to the visual cycle, by high-performance liquid chromatography. J Chromatogr. 1979;168:125–32.
28 Diacylglycerol O-acyltransferase type-1 synthesizes retinyl esters in the retina and retinal pigment epithelium. PLoS One. 2015;10(5):e0125921.
29 . Purified RPE65 shows isomerohydrolase activity after reassociation with a phospholipid membrane. Febs J. 2009;276:3020–30.
30 . Identification of the key residues determining the product specificity of isomerohydrolase. Biochemistry. 2012;51:4217–25.
31 Rpe65 is a retinyl ester binding protein that presents insoluble substrate to the isomerase in retinal pigment epithelial cells. J Biol Chem. 2004;279(1):635–43.
32 . Dark isomerization of retinals in the presence of phosphatidylethanolamine. Eur J Biochem. 1980;106:119–28.
33 . Human cellular retinaldehyde-binding protein has secondary thermal 9-cis-retinal isomerase activity. J Am Chem Soc. 2013;136:137–46.
34 . Vitamin A and vision. Subcell Biochem. 2016;81:231–59.
35 . Occurrence and conversion of anhydrolutein into dehydroretinol in a freshwater fish. Br J Nutr. 1975;33:319–27.
36 . Conversion of carotenoids to 3-dehydroretinol (vitamin A2) in the mouse. Nature. 1965;206:1254–5.
37 . Assessment of dietary vitamin A intake (retinol, alpha-carotene, beta-carotene, beta-cryptoxanthin) and its sources in the National Survey of Dietary Intake in Spain (2009–2010). Int J Food Sci Nutr. 2015;66:706–12.
38 Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans. Mol Nutr Food Res. 2017;61:1600685.
39 Sources of alpha-, beta-, gamma-, delta- and epsilon-carotenes: a twentieth century review. Rev Bras Farmacogn. 2008;18(1):135–54.
40 . Carotenoids and their isomers: color pigments in fruits and vegetables. Molecules. 2011;16:1710–38.
41 . Scientific opinion on the re-evaluation of ß-apo-8´-carotenal (E160e) as a food additive. EFSA J. 2012;10:2499.
42 . Excentral cleavage of beta-carotene in vivo in a healthy man. Am J Clin Nutr. 2007;85:770–7.
43 . Laying down specifications for food additives listes in annex II and II to regulation No 1333/2008 of the European parliament and of the council.Official Journal of the European Union. 2012, L83/1.
44 . Laying down specifications for food additives listes in annex II and II to regulation No 1333/2008 of the European parliament and of the council.Official Journal of the European Union. 2020, 2020/771.
45 . Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1). J Biol Chem. 2013;288:37094–103.
46 Substrate specificity of purified recombinant chicken beta-carotene 9',10'-oxygenase (BCO2). J Biol Chem. 2016;291:14609–19.
47 . The human enzyme that converts dietary provitamin a carotenoids to vitamin a is a dioxygenase. J Biol Chem. 2013;289:13661–6.
48 . Vitamin D deficiency. N Engl J Med. 2007;357:266–81.
49 . Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013;98:973–9.
50 . Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29:664–73.
51 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992;68(2):397–406.
52 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992;355:359–61.
53 Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA. 1993;90(1):30–4.
54 . Nonenzymatic isomerization of all-trans- and 13-cis-retinoids catalyzed by sulfhydryl groups. Drug Metab Dispos. 1986;14:698–702.
55 9-cis-13,14-dihydroretinoic acid is an endogenous retinoid acting as RXR ligand in mice. PLoS Genet. 2015;11(6):e1005213.
56 . An Endogenous mammalian retinoid X receptor ligand, at last!. ChemMedChem. 2016;11:1027–37.
57 . Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol. 2019;491:110436.