Zeaxanthin

Lutein and zeaxanthin have identical chemical formulas and are isomers, but they are not stereoisomers. The only difference between them is in the location of the double bond in one of the end rings. This difference gives lutein three chiral centers whereas zeaxanthin has two. Because of symmetry, the (3R,3′S) and (3S,3′R) stereoisomers of zeaxanthin are identical. Therefore, zeaxanthin has only three stereoisomeric forms. The (3R,3′S) stereoisomer is called meso-zeaxanthin.

The principal natural form of zeaxanthin is (3R,3′R)-zeaxanthin. The macula mainly contains the (3R,3′R)- and meso-zeaxanthin forms, but it also contains much smaller amounts of the third (3S,3′S) form.{{Cite journal | pmid = 23703634 | year = 2013 | last1 = Nolan | first1 = J. M. | title = What is meso-zeaxanthin, and where does it come from? | journal = Eye | volume = 27 | issue = 8 | pages = 899–905 | last2 = Meagher | first2 = K | last3 = Kashani | first3 = S | last4 = Beatty | first4 = S | doi = 10.1038/eye.2013.98 | pmc = 3740325 }} Evidence exists that a specific zeaxanthin-binding protein recruits circulating zeaxanthin and lutein for uptake within the macula.{{Cite journal | pmid = 20820671 | year = 2010 | last1 = Li | first1 = B | title = Human ocular carotenoid-binding proteins | journal = Photochemical & Photobiological Sciences | volume = 9 | issue = 11 | pages = 1418–25 | last2 = Vachali | first2 = P | last3 = Bernstein | first3 = P. S. | doi = 10.1039/c0pp00126k | pmc = 3938892 | bibcode = 2010PhPhS...9.1418L }}

Due to the commercial value of carotenoids, their biosynthesis has been studied extensively in both natural products and non-natural (heterologous) systems such as the bacteria Escherichia coli and yeast Saccharomyces cerevisiae. Zeaxanthin biosynthesis proceeds from beta-carotene via the action of a single protein, known as a beta-carotene hydroxylase, that is able to add a hydroxyl group (-OH) to carbon 3 and 3′ of the beta-carotene molecule. Zeaxanthin biosynthesis therefore proceeds from beta-carotene to zeaxanthin (a di-hydroxylated product) via beta-cryptoxanthin (the mono hydroxylated intermediate). Although functionally identical, several distinct beta-carotene hydroxylase proteins are known.

Due to the nature of zeaxanthin, relative to astaxanthin (a carotenoid of significant commercial value) beta-carotene hydroxylase proteins have been studied extensively.{{cite journal|last=Scaife|first=Mark A.|author2=Ma, Cynthia A. |author3=Ninlayarn, Thanyanun |author4=Wright, Phillip C. |author5= Armenta, Roberto E. |display-authors=3 |title=Comparative Analysis of β-Carotene Hydroxylase Genes for Astaxanthin Biosynthesis|journal=Journal of Natural Products|date=22 May 2012|pages=1117–24|doi=10.1021/np300136t|pmid=22616944|volume=75|issue=6}}

Several observational studies have provided preliminary evidence for high dietary intake of foods including lutein and zeaxanthin with lower incidence of age-related macular degeneration (AMD), most notably the Age-Related Eye Disease Study (AREDS2).{{cite web|url=https://nei.nih.gov/news/pressreleases/050513|title=NIH study provides clarity on supplements for protection against blinding eye disease|date=5 May 2013|access-date=10 August 2017|publisher=US National Eye Institute, National Institutes of Health, Bethesda, MD|archive-date=15 August 2019|archive-url=https://web.archive.org/web/20190815055737/https://nei.nih.gov/news/pressreleases/050513|url-status=dead}}{{cite journal|pmc=4698241|year=2015|last1=Bernstein|first1=P. S.|title=Lutein, Zeaxanthin, and meso-Zeaxanthin: The Basic and Clinical Science Underlying Carotenoid-based Nutritional Interventions against Ocular Disease|journal=Progress in Retinal and Eye Research|volume=50|pages=34–66|last2=Li|first2=B|last3=Vachali|first3=P. P.|last4=Gorusupudi|first4=A|last5=Shyam|first5=R|last6=Henriksen|first6=B. S.|last7=Nolan|first7=J. M.|display-authors=3|doi=10.1016/j.preteyeres.2015.10.003|pmid=26541886}} Because foods high in one of these carotenoids tend to be high in the other, research does not separate effects of one from the other.{{cite journal |vauthors=Krishnadev N, Meleth AD, Chew EY | title = Nutritional supplements for age-related macular degeneration | journal = Current Opinion in Ophthalmology | volume = 21 | issue = 3 | pages = 184–9 |date=May 2010 | pmid = 20216418 | pmc = 2909501 | doi = 10.1097/ICU.0b013e32833866ee }}{{cite journal |vauthors=SanGiovanni JP, Chew EY, Clemons TE, etal | title = The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22 | journal = Archives of Ophthalmology | volume = 125 | issue = 9 | pages = 1225–1232 |date=September 2007 | pmid = 17846363 | doi = 10.1001/archopht.125.9.1225 | doi-access = }}

• Three subsequent meta-analyses of dietary lutein and zeaxanthin concluded that these carotenoids lower the risk of progression from early stage AMD to late stage AMD.{{cite journal |vauthors=Liu R, Wang T, Zhang B, Qin L, Wu C, Li Q, Ma L |display-authors=3 |title=Lutein and zeaxanthin supplementation and association with visual function in age-related macular degeneration |journal=Invest. Ophthalmol. Vis. Sci. |volume=56 |issue=1 |pages=252–8 |year=2014 |pmid=25515572 |doi=10.1167/iovs.14-15553 }}{{cite journal |vauthors=Wang X, Jiang C, Zhang Y, Gong Y, Chen X, Zhang M |display-authors=3 |title=Role of lutein supplementation in the management of age-related macular degeneration: meta-analysis of randomized controlled trials |journal=Ophthalmic Res. |volume=52 |issue=4 |pages=198–205 |year=2014 |pmid=25358528 |doi=10.1159/000363327 |s2cid=5055854 }}{{cite journal |vauthors=Ma L, Dou HL, Wu YQ, Huang YM, Huang YB, Xu XR, Zou ZY, Lin XM |display-authors=3 |title=Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis |journal=Br. J. Nutr. |volume=107 |issue=3 |pages=350–9 |year=2012 |pmid=21899805 |doi=10.1017/S0007114511004260 |doi-access=free }}
• A 2023 (updated) Cochrane review of 26 studies from several countries, however, concluded that dietary supplements containing zeaxanthin and lutein have little to no influence on the progression of AMD.{{Cite journal |last1=Evans |first1=Jennifer R. |last2=Lawrenson |first2=John G. |date=2023-09-13 |title=Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration |journal=The Cochrane Database of Systematic Reviews |volume=2023 |issue=9 |pages=CD000254 |doi=10.1002/14651858.CD000254.pub5 |issn=1469-493X |pmc=10498493 |pmid=37702300 }} In general, there remains insufficient evidence to assess the effectiveness of dietary or supplemental zeaxanthin or lutein in treatment or prevention of early AMD.

As for cataracts, two meta-analyses confirm a correlation between high serum concentrations of lutein and zeaxanthin and a decrease in the risk of nuclear cataract, but not cortical or subcapsular cataract. The reports did not separate a zeaxanthin effect from a lutein effect.{{cite journal |vauthors=Liu XH, Yu RB, Liu R, Hao ZX, Han CC, Zhu ZH, Ma L |display-authors=3 |title=Association between lutein and zeaxanthin status and the risk of cataract: a meta-analysis |journal=Nutrients |volume=6 |issue=1 |pages=452–65 |year=2014 |pmid=24451312 |pmc=3916871 |doi=10.3390/nu6010452 |doi-access=free }}{{cite journal |vauthors=Ma L, Hao ZX, Liu RR, Yu RB, Shi Q, Pan JP |display-authors=3 |title=A dose-response meta-analysis of dietary lutein and zeaxanthin intake in relation to risk of age-related cataract |journal=Graefes Arch. Clin. Exp. Ophthalmol. |volume=252 |issue=1 |pages=63–70 |year=2014 |pmid=24150707 |doi=10.1007/s00417-013-2492-3 |s2cid=13634941 }} The AREDS2 trial enrolled subjects at risk for progression to advanced age-related macular degeneration. Overall, the group getting lutein (10 mg) and zeaxanthin (2 mg) did not reduce the need for cataract surgery.{{cite journal |vauthors=Chew EY, SanGiovanni JP, Ferris FL, Wong WT, Agron E, Clemons TE, Sperduto R, Danis R, Chandra SR, Blodi BA, Domalpally A, Elman MJ, Antoszyk AN, Ruby AJ, Orth D, Bressler SB, Fish GE, Hubbard GB, Klein ML, Friberg TR, Rosenfeld PJ, Toth CA, Bernstein P |display-authors=3 |title=Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4 |journal=JAMA Ophthalmol |volume=131 |issue=7 |pages=843–50 |year=2013 |pmid=23645227 |doi=10.1001/jamaophthalmol.2013.4412 |pmc=6774801 |doi-access=free }} Any benefit is more likely to be apparent in subpopulations of individuals exposed to high oxidative stress, such as heavy smokers, alcoholics or those with low dietary intake of carotenoid-rich foods.{{cite journal |vauthors=Fernandez MM, Afshari NA | title = Nutrition and the prevention of cataracts | journal = Current Opinion in Ophthalmology | volume = 19 | issue = 1 | pages = 66–70 |date=January 2008 | pmid = 18090901 | doi = 10.1097/ICU.0b013e3282f2d7b6 | s2cid = 25735519 }}

In 2005, the US Food and Drug Administration rejected a Qualified Health Claims application by Xangold, citing insufficient evidence supporting the use of a lutein- and zeaxanthin-containing supplement in prevention of AMD.{{cite web|publisher=US FDA, Qualified Health Claims|url=https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073291.htm |title=Letter of Denial - Xangold Lutein Esters, Lutein, or Zeaxanthin and Reduced Risk of Age-related Macular Degeneration or Cataract Formation (Docket No. 2004Q-0180|date=19 December 2005}} Dietary supplement companies in the U.S. are allowed to sell lutein and lutein plus zeaxanthin products using dietary supplement, such as "Helps maintain eye health", as long as the FDA disclaimer statement ("These statements have not been evaluated...") is on the label. In Europe, as recently as 2014, the European Food Safety Authority reviewed and rejected claims that lutein or lutein plus zeaxanthin improved vision.{{cite journal|title=Scientific Opinion on the substantiation of a health claim related to a combination of lutein and zeaxanthin and improved vision under bright light conditions pursuant to Article 13(5) of Regulation (EC) No 1924/2006|journal=EFSA Journal|volume=12|issue=7|year=2014|pages=3753|issn=1831-4732|doi=10.2903/j.efsa.2014.3753|doi-access=free}}

Zeaxanthin is the pigment that gives paprika, corn, saffron, wolfberries (goji), and many other plants their characteristic colors of red, orange or yellow. Spirulina is also a rich source and can serve as a dietary supplement.{{Cite journal | last1 = Yu | first1 = B. | last2 = Wang | first2 = J. | last3 = Suter | first3 = P. M. | last4 = Russell | first4 = R. M. | last5 = Grusak | first5 = M. A. | last6 = Wang | first6 = Y. | last7 = Wang | first7 = Z. | last8 = Yin | first8 = S. | last9 = Tang | first9 = G. | doi = 10.1017/S0007114511005885 | title = Spirulina is an effective dietary source of zeaxanthin to humans | journal = British Journal of Nutrition | volume = 108 | issue = 4 | pages = 611–619 | year = 2012 | pmid = 22313576 | display-authors=3 | doi-access = free }} Zeaxanthin breaks down to form picrocrocin and safranal, which are responsible for the taste and aroma of saffron.{{Cite journal|title = Novel carotenoid cleavage dioxygenase catalyzes the first dedicated step in saffron crocin biosynthesis|journal = Proceedings of the National Academy of Sciences|date = 2014-08-19|issn = 0027-8424|pmc = 4143034|pmid = 25097262|pages = 12246–12251|volume = 111|issue = 33|doi = 10.1073/pnas.1404629111|language = en|first1 = Sarah|last1 = Frusciante|first2 = Gianfranco|last2 = Diretto|first3 = Mark|last3 = Bruno|first4 = Paola|last4 = Ferrante|first5 = Marco|last5 = Pietrella|first6 = Alfonso|last6 = Prado-Cabrero|first7 = Angela|last7 = Rubio-Moraga|first8 = Peter|last8 = Beyer|first9 = Lourdes|last9 = Gomez-Gomez|display-authors=3|bibcode = 2014PNAS..11112246F|doi-access = free}}

Dark green leaf vegetables, such as kale, spinach, turnip greens, collard greens, romaine lettuce, watercress, Swiss chard and mustard greens are rich in lutein{{cite web|url=http://nutritiondata.self.com/foods-000138000000000000000-1w.html|title=Foods highest in lutein-zeaxanthin per 100 grams|publisher=Conde Nast for the USDA National Nutrient Database, release SR-21|date=2014|access-date=23 December 2015}} but contain little to no zeaxanthin, with the exception of scallions cooked in oil. Orange bell peppers (but not green, red, or yellow) are rich in zeaxanthin.

An acceptable daily intake level for zeaxanthin was proposed as 0.75 mg/kg of body weight/day, or 53 mg/day for a 70 kg adult.{{cite journal | vauthors = Edwards JA | title = Zeaxanthin: Review of Toxicological Data and Acceptable Daily Intake | journal = Journal of Ophthalmology | volume = 2016 | pages = 1–15 | year = 2016 | pmid = 26885380 | pmc = 4738691 | doi = 10.1155/2016/3690140 | quote =
• In their evaluation of the safety of synthetic zeaxanthin as a Novel Food, the EFSA NDA Scientific Panel [37] applied a 200-fold safety factor to this NOAEL to define an ADI of 0.75 mg/kg bw/day, or 53 mg/day for a 70 kg adult.
• Formulated zeaxanthin was not mutagenic or clastogenic in a series of in vitro and in vivo tests for genotoxicity.
• Information from human intervention studies also supports that an intake higher than 2 mg/day is safe, and an intake level of 20 mg/day for up to 6 months was without adverse effect.| doi-access = free }} In humans, an intake of 20 mg/day for up to six months had no adverse effects. As of 2016, neither the U.S. Food and Drug Administration nor the European Food Safety Authority had set a Tolerable Upper Intake Level (UL) for lutein or zeaxanthin.

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{{Carotenoids}}

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