Zeaxanthin (derived from: zea mays “corn” and xanthós (Greek) “sandy yellow, blond”) is a well-known representative of the substance class of carotenoids, which as lipophilic (fat-soluble) pigment dyes give numerous plants their yellow, orange and reddish colors. Carotenoids belong to the large group of secondary plant substances and thus represent “anutritive ingredients” (bioactive substances that do not have a life-sustaining nutritive function but are characterized by their health-promoting effects). According to the subdivision of carotenoids into carotenes, such as alpha-carotene, beta-carotene and lycopene, which consist of carbon (C) and hydrogen (H), and xanthophylls, such as lutein and beta-cryptoxanthin, which contain oxygen (O) in addition to C and H atoms, zeaxanthin belongs to the latter. Structural feature of zeaxanthin is the symmetrical, polyunsaturated polyene structure (organic compound with multiple carbon-carbon (C-C) double bonds) consisting of 8 isoprenoid units and 11 conjugated double bonds (multiple consecutive double bonds separated by exactly one single bond). An oxygen-substituted beta-ionone ring (O-substituted conjugated trimethylcyclohexene ring) is attached to each end of the isoprenoid chain. The system of conjugated double bonds is responsible for both the yellow-orange color and some physicochemical properties of zeaxanthin, which are directly related to their biological effects. Despite the polar OH group on both ring systems, zeaxanthin is markedly lipophilic (fat soluble), which affects intestinal (concerning the intestine) absorption and distribution in the organism. Zeaxanthin has a high structural similarity with lutein. Both carotenoids are dicyclic xanthophylls with the molecular formula C40H56O2 and a molar mass of 568.8 g/mol, differing only in the position of a double bond in one of the two trimethylcyclohexene rings. For this reason, zeaxanthin and lutein represent functionally closely related isomers (compounds of the same molecular formula but with different shapes) and are always found together in the organism. Zeaxanthin can occur in different geometric forms (cis/trans isomerism, (R)-/(S)-configuration), which are convertible into each other. In plants, the dicyclic xanthophyll is predominantly (~ 98%) present as a stable (R)-all-trans isomer – (3R,3’R)-all-trans-zeaxanthin. In the human organism, different isomeric forms can co-occur – cis-/trans-, (3R,3’R)-, (3S,3’S)- and meso- (3R,3’S)- or (3S,3’R)-zeaxanthin. Exogenous influences, such as heat and light, can alter the configuration of zeaxanthin from foods. The cis-isomers of zeaxanthin, in contrast to the all-trans isomers, exhibit a lower tendency to crystallize and aggregate, better solubility, higher absorption rate, and faster intracellular and extracellular transport. Of the approximately 700 carotenoids identified, about 60 are convertible to vitamin A (retinol) by human metabolism and thus exhibit provitamin A activity. In zeaxanthin, because both ring systems contain oxygen, it is not a provitamin A.
Synthesis
Carotenoids are synthesized (formed) by all plants, algae, and bacteria capable of photosynthesis. In higher plants, carotenoid synthesis occurs in photosynthetically active tissues as well as in petals, fruits, and pollen. Finally, carotenoids, especially xanthophylls, have been discovered in all leaf parts studied so far, particularly those with a dicyclic structure and a hydroxy (OH) group at C-3 or C-3′ position – corresponding to zeaxanthin and lutein. The biosynthesis of zeaxanthin occurs from beta-cryptoxanthin by hydroxylation (reaction to introduce one or more hydroxyl groups) of the unsubstituted beta-ionone ring by beta-carotene hydroxylase – enzymatic introduction of an OH group.In the cells of the plant organism, zeaxanthin is stored in the chromoplasts (plastids colored orange, yellow, and reddish by carotenoids in petals, fruits, or storage organs (carrots) of plants) and chloroplasts (organelles of the cells of green algae and higher plants that perform photosynthesis) – incorporated in a complex matrix of proteins, lipids, and/or carbohydrates. While xanthophyll in the chromoplasts of petals and fruits serves to attract animals – for pollen transfer and seed dispersal – in the chloroplasts of plant leaves it provides protection against photooxidative damage (oxidation reactions caused by light) as a component of light-harvesting complexes. Antioxidant protection is achieved by so-called quenching (detoxification, inactivation) of reactive oxygen compounds (1O2, singlet oxygen), where zeaxanthin directly absorbs (takes up) radiant energy via the triplet state and deactivates it via heat release. Since the ability to quench increases with the number of double bonds, zeaxanthin with its 11 double bonds has a high quenching activity. Zeaxanthin is widely distributed in nature and is the most abundant carotenoid in plant foods along with alpha- and beta-carotene, beta-cryptoxanthin, lycopene as well as lutein. It is always accompanied by its isomer lutein and is found with it predominantly in dark green leafy vegetables, such as cabbage, especially kale, spinach, lettuce, turnip greens, and parsley, although the content can vary greatly depending on variety, season, maturity, growth, harvest, and storage conditions, and in different parts of the plant. For example, the outer leaves of cabbage and lettuce contain significantly more zeaxanthin than the inner leaves. High zeaxanthin contents can also be detected in corn – where zeaxanthin is the primary yellow pigment – peppers and saffron. The dicyclic xanthophyll enters the animal organism via plant feed, where it accumulates in the blood, skin or feathers and has an attractant, warning or camouflage function. For example, zeaxanthin is responsible for the yellow color of the thighs and claws of chickens, geese and ducks. The color of egg yolks is also due to the presence of xanthophylls, especially lutein and zeaxanthin – in a ratio of about 4:1. For medicinal purposes – drugs, food supplements – and for use in the food and feed industry – food colorant (E 161h), additive in animal feed (premixes and feed mixtures) to achieve coloration in animal products – zeaxanthin is produced synthetically or obtained from zeaxanthin-containing algae and plant parts, for example, from the petals of Tagetes (marigold, herbaceous plant with lemon-yellow to brown-red inflorescences), by extraction. Using genetic engineering methods, it is possible to influence the content and pattern of carotenoids in plants and thus to specifically increase zeaxanthin concentrations.
Resorption
Because of its lipophilic (fat-soluble) nature, zeaxanthin is absorbed (taken up) in the upper small intestine during fat digestion. This necessitates the presence of dietary fats (3-5 g/meal) as transporters, bile acids to solubilize (increase solubility) and form micelles, and esterases (digestive enzymes) to cleave zeaxanthin esterified with fatty acids. After release from the dietary matrix, zeaxanthin combines in the small intestinal lumen with other lipophilic substances and bile acids to form mixed micelles (spherical structures 3-10 nm in diameter in which the lipid molecules are arranged in such a way that the water-soluble molecule portions are turned outward and the water-insoluble molecule portions are turned inward) – micellar phase for solubilization (increase in solubility) of lipids – which are absorbed into the enterocytes (cells of the small intestinal epithelium) of the duodenum (duodenum) and jejunum (jejunum) via a passive diffusion process. The absorption rate of zeaxanthin from plant foods varies widely intra- and interindividually, ranging from 30 to 60% depending on the proportion of fat consumed at the same time.In terms of their promoting influence on zeaxanthin absorption, saturated fatty acids are far more effective than polyunsaturated fatty acids (polyene fatty acids, PFS), which can be justified as follows:
- PFS increase the size of mixed micelles, which decreases the diffusion rate
- PFS alter the charge of the micellar surface, decreasing the affinity (binding strength) to enterocytes (cells of the small intestinal epithelium)
- PFS (omega-3 and -6 fatty acids) occupy more space than saturated fatty acids in lipoproteins (aggregates of lipids and proteins – micelle-like particles – that serve to transport lipophilic substances in the blood), thus limiting the space for other lipophilic molecules, including zeaxanthin
- PFS, especially omega-3 fatty acids, inhibit lipoprotein synthesis.
Zeaxanthin bioavailability is dependent on the following endogenous and exogenous factors in addition to fat intake [4, 11, 14, 15, 21, 29, 48, 55-57, 72, 76]:
- Amount of alimentary (dietary) zeaxanthin intake – as the dose increases, the relative bioavailability of the carotenoid decreases
- Isomeric form – zeaxanthin, unlike other carotenoids such as beta-carotene, is better absorbed in its cis configuration than in its all-trans form; heat treatment, such as cooking, promotes conversion from all-trans to cis zeaxanthin
- Food source – from supplements (isolated zeaxanthin in oily solution – free present or esterified with fatty acids), the carotenoid is more available than from plant foods (native, complexed zeaxanthin), as evidenced by a significantly higher increase in serum zeaxanthin levels after ingestion of supplements compared with ingestion of equal amounts from fruits and vegetables
- Food matrix in which zeaxanthin is incorporated – from processed vegetables (mechanical comminution, heat treatment, homogenization), zeaxanthin is significantly better absorbed (> 15%) than from raw foods (< 3%), because the carotenoid in raw vegetables is crystalline in the cell and enclosed in a solid cellulose and/or protein matrix that is difficult to absorb; Since zeaxanthin is sensitive to heat, foods containing zeaxanthin should be prepared gently to minimize loss
- Interactions with other food ingredients
- Dietary fiber, such as pectins from fruits, decreases the bioavailability of zeaxanthin by forming poorly soluble complexes with the carotenoid
- Olestra (synthetic fat substitute consisting of esters of sucrose and long-chain fatty acids (→ sucrose polyester), which cannot be cleaved by endogenous lipases (fat-cleaving enzymes) due to steric hindrance and is excreted unchanged) reduces zeaxanthin absorption; according to Koonsvitsky et al (1997), a daily intake of 18 g of olestra over a period of 3 weeks results in a 27% drop in serum carotenoid levels
- Phytosterols and -stanols (chemical compounds from the class of sterols found in fatty plant parts, such as seeds, sprouts and seeds, which are very similar to the structure of cholesterol and competitively inhibit its absorption) can impair the intestinal absorption of zeaxanthin; so the regular use of phytosterol-containing spreads, such as margarine, can lead to a moderately lowered (by 10-20%) carotenoid serum levels; by a simultaneous increased daily intake of carotenoid-rich fruits and vegetables, a reduction in serum carotenoid concentrations can be prevented by the consumption of phytosterol-containing margarine.
- Intake of carotenoid mixtures, such as zeaxanthin, lutein, beta-carotene, cryptoxanthin, and lycopene, can both inhibit and promote intestinal zeaxanthin uptake-at the level of incorporation into mixed micelles in the intestinal lumen, enterocytes during intracellular transport, and incorporation into lipoproteins-with strong interindividual differences; according to Olsen (1994), administration of high pharmacological doses of beta-carotene results in decreased zeaxanthin absorption and a decrease in serum zeaxanthin levels – presumably due to kinetic displacement processes along the intestinal mucosa (intestinal lining); thereby, the preferential monosupplementation of high doses of beta-carotene appears to inhibit intestinal absorption, especially of those carotenoids that have a higher protective potential than beta-carotene, such as zeaxanthin, lutein, and lycopene, and are present in significant amounts in serum; Wahlquist et al (1994) did not find any effect on zeaxanthin serum levels when 20 mg of beta-carotene was administered daily for a period of one year
- Proteins and vitamin E increase zeaxanthin absorption.
- Individual digestive performance, such as mechanical comminution in the upper digestive tract, gastric pH, bile flow – thorough chewing and low gastric juice pH promote cell disruption and release of bound and esterified zeaxanthin, respectively, which increases the bioavailability of the carotenoid; decreased bile flow decreases bioavailability due to impaired micelle formation
- Supply status of the organism
- Genetic factors
Transport and distribution in the body
In enterocytes (cells of the small intestinal epithelium) of the upper small intestine, zeaxanthin is incorporated into chylomicrons (CM, lipid-rich lipoproteins) along with other carotenoids and lipophilic substances, such as triglycerides, phospholipids, and cholesterol, which are secreted (secreted) into the interstitial spaces of enterocytes by exocytosis (transport of substances out of the cell) and transported away via the lymph. Via the truncus intestinalis (unpaired lymphatic collecting trunk of the abdominal cavity) and ductus thoracicus (lymphatic collecting trunk of the thoracic cavity), the chylomicrons enter the subclavian vein (subclavian vein) and jugular vein (jugular vein), respectively, which converge to form the brachiocephalic vein (left side) – angulus venosus (venous angle). The venae brachiocephalicae of both sides unite to form the unpaired superior vena cava (superior vena cava), which opens into the right atrium of the heart (atrium cordis dextrum). Chylomicrons are delivered into the peripheral circulation by the pumping force of the heart. By a single administration of the halophilic marine alga Dunaliella salina, which can produce considerable amounts of carotenoids, including (all-trans, cis) beta-carotene, alpha-carotene, cryptoxanthin, lycopene, lutein, and zeaxanthin, it has been shown in the blood of healthy individuals that chylomicrons preferentially store the xanthophylls lutein and zeaxanthin over carotenes such as alpha- and beta-carotene. The cause is discussed to be the higher polarity of xanthophylls due to their free hydroxy (OH) groups, which leads to a more efficient uptake of zeaxanthin into both mixed micelles and lipoproteins compared to beta-carotene. Chylomicrons have a half-life (time in which a value that decreases exponentially with time is halved) of approximately 30 minutes and are degraded to chylomicron remnants (CM-R, low-fat chylomicron remnants) during transport to the liver. In this context, lipoprotein lipase (LPL) plays a crucial role, which is located on the surface of endothelial cells of blood capillaries and leads to the uptake of free fatty acids and small amounts of zeaxanthin into various tissues, for example muscle, adipose tissue and mammary gland, by lipid cleavage. However, the majority of zeaxanthin remains in CM-R, which binds to specific receptors in the liver and is taken up into the parenchymal cells of the liver via receptor-mediated endocytosis (invagination of the cell membrane → strangulation of CM-R-containing vesicles (cell organelles) into the cell interior). In the liver cells, zeaxanthin is partly stored, and another part is incorporated into VLDL (very low density lipoproteins), through which the carotenoid reaches extrahepatic tissues via the bloodstream.As VLDL circulating in the blood binds to peripheral cells, the lipids are cleaved by the action of LPL and the lipophilic substances released, including zeaxanthin, are internalized (taken up internally) by passive diffusion. This results in catabolism (degradation) of VLDL to IDL (intermediate density lipoproteins). IDL particles can either be taken up by the liver in a receptor-mediated manner and degraded there, or metabolized (metabolized) in the blood plasma by a triglyceride lipase (fat-splitting enzyme) to cholesterol-rich LDL (low density lipoproteins). Zeaxanthin bound to LDL is taken up into liver and extrahepatic tissues via receptor-mediated endocytosis on the one hand and transferred to HDL (high density lipoproteins) on the other hand, which are involved in the transport of zeaxanthin and other lipophilic molecules, especially cholesterol, from peripheral cells back to the liver. A complex mixture of carotenoids is found in human tissues and organs, which is subject to strong individual variations both qualitatively (pattern of carotenoids) and quantitatively (concentration of carotenoids). Lutein and zeaxanthin, alpha- and beta-carotene, lycopene, and alpha- and beta-cryptoxanthin are the main carotenoids in the organism and contribute about 80% to the total carotenoid content.Zeaxanthin is found – always accompanied by lutein – in all tissues and organs of humans, with significant differences in concentration. In addition to liver, adrenal glands, testes (testicles) and ovaries (ovaries) – especially the corpus luteum (corpus luteum) – especially the yellow spot of the eye (lat. : macula lutea, thin, transparent, light-sensitive nervous tissue with the highest density of photoreceptor cells (rods and cones) → “the point of sharpest vision”) has a high content of zeaxanthin. The yellow spot is located in the center of the retina temporal (dormant) to the optic nerve papilla and is 3-5 mm in diameter. From the outer (perifovea) to the inner area (parafovea) of the macula, the amount of rods decreases, so that in the center of the yellow spot, in the fovea centralis (shallow depression – “visual pit”, area of sharpest vision (highest spatial resolution)), there are exclusively cones (visual cells responsible for color perception). As the amount of cones increases from the perifovea toward the fovea centralis, the content of lutein and zeaxanthin also increases sharply – concentration of macular pigment (lutein and zeaxanthin) to an area of circa 1.5 mm radius around the fovea centralis. The macula contains lutein and zeaxanthin as the only carotenoids, with zeaxanthin bound to a specific binding protein (GSTP1, class pi glutathione S-transferase) and occurring mainly in the form of its (3R,3’R) isomer and as meso-zeaxanthin ((3R,3’S)- and (3S,3’R)-zeaxanthin, respectively). It is suggested that meso-zeaxanthin is a conversion product of lutein. In the fovea centralis, lutein appears to undergo a chemical reaction. It could be oxidized to oxo- lutein by reactive compounds and subsequently reduced to zeaxanthin and meso-zeaxanthin, respectively. The enzymes required for this have not yet been identified. Since the retina of children contains more lutein and less meso-zeaxanthin compared to that of adults, this mechanism does not yet seem to be as pronounced in the infant organism.Lutein and zeaxanthin give the yellow spot its color and are functionally significant as light filters and antioxidants. Both xanthophylls, due to their conjugated double bonds, can absorb (take up) with high efficiency the blue (high-energy short-wavelength) and potentially harmful portion of visible light, thus protecting photoreceptors from photooxidative damage, which plays a role in the pathogenesis (development) of senile (age-related) macular degeneration (AMD) [4, 21, 22, 28, 35, 36, 40, 59, 61-63, 65, 69]. AMD is characterized by a gradual loss of retinal cell function and is the leading cause of blindness in people aged >50 years in developed countries. Studies on deceased AMD patients showed that their retinas had significantly decreased zeaxanthin and lutein contents.According to epidemiological studies, an increased intake of lutein and zeaxanthin (at least 6 mg/day from fruits and vegetables) is associated with an increase in macular pigment density and up to 82% reduced risk of developing AMD [3, 7, 21, 29, 37, 40, 42, 43, 59, 63-67, 69]. Finally, increased dietary intake of both xanthophylls can significantly increase their yellow spot concentrations, which correlate with serum lutein and zeaxanthin levels. The accumulation processes require up to several months, so the increased lutein and zeaxanthin intake must be long-term. In corresponding studies, the concentrations of both xanthophylls had not significantly increased after one month. The data available so far indicate not only a reduction in the risk of AMD but also a positive influence on the course of AMD by lutein and zeaxanthin, so that the xanthophylls could be useful both in the prevention and in the therapy of this eye disease. In addition to the macula lutea, zeaxanthin is also found in the lens of the eye, where it and lutein are the only carotenoids present. By inhibiting photochemical generation of reactive oxygen species and thus preventing, among other things, modification of lens proteins and accumulation of glycoproteins and oxidation products, the dicyclic xanthophylls may prevent or slow the progression (progression) of cataract (cataract, clouding of the crystalline lens) [17, 19-21, 26, 31, 53, 55]. This is supported by several prospective studies in which an increased intake of foods rich in lutein and zeaxanthin, such as spinach, kale and broccoli, was able to reduce the probability of developing a cataract or requiring a cataract extraction (surgical procedure in which the clouded lens of the eye is removed and replaced by an artificial lens) by 18-50%. A prerequisite is a regular and long-term high dietary intake of lutein and zeaxanthin to achieve sufficient concentrations of xanthophylls in the eye. High lutein and zeaxanthin levels in the retina correlate with transparent eye lenses. In terms of absolute concentration and tissue contribution to total body weight, zeaxanthin is largely localized in adipose tissue (approximately 65%) and liver. In addition, zeaxanthin is found marginally in lung, brain, heart, skeletal muscle, and skin. There is a direct but not linear correlation (relationship) between tissue storage and oral intake of the carotenoid. Thus, zeaxanthin is released from tissue depots only very slowly over several weeks after cessation of intake. In the blood, zeaxanthin is transported by lipoproteins composed of lipophilic molecules and apolipoproteins (protein moiety, function as structural scaffold and/or recognition and docking molecule, for example for membrane receptors), such as Apo A-I, B-48, C-II, D and E. Carotenoid is 75-80% bound to LDL, 10-25% bound to HDL, and 5-10% bound to VLDL. In a normal mixed diet, serum zeaxanthin concentrations range from 0.05-0.5 µmol/l and vary according to sex, age, health status, total body fat mass, and levels of alcohol and tobacco consumption. Supplementation of standardized doses of zeaxanthin could confirm that large interindividual variations occur with respect to zeaxanthin serum concentrations.In human serum and breast milk, 34 of the approximately 700 known carotenoids, including 13 geometric all-trans isomers, have been identified so far. Among these, zeaxanthin, lutein, cryptoxanthin, alpha- and beta-carotene, and lycopene have been detected most frequently.
Excretion
Unabsorbed zeaxanthin leaves the body in the feces (stool), whereas its metabolites are eliminated in the urine. To convert the metabolites into an excretable form, they undergo biotransformation, as do all lipophilic (fat-soluble) substances. Biotransformation occurs in many tissues, especially in the liver, and can be divided into two phases
- In phase I, the metabolites of zeaxanthin are hydroxylated (insertion of an OH group) to increase solubility by the cytochrome P-450 system
- In phase II, conjugation with strongly hydrophilic (water-soluble) substances takes place – for this purpose, glucuronic acid is transferred to the previously inserted OH group of the metabolites with the help of glucuronyltransferase
Much of the metabolites of zeaxanthin has not yet been elucidated. However, it can be assumed that the excretion products are predominantly glucuronidated metabolites. After a single administration, the residence time of carotenoids in the body is between 5-10 days.
