Lutein (Latin : luteus “yellow”) is a well-known representative of carotenoids (lipophilic (fat-soluble) pigment dyes of plant origin) – those secondary plant compounds (bioactive substances with health-promoting effects – “anutritive ingredients”) that give plant organisms their yellow to reddish color. Lutein consists of a total of 40 carbon (C-), 56 hydrogen (H-) and 2 oxygen (O-) atoms – molecular formula C40H56O2. Thus, lutein, like zeaxanthin and beta-cryptoxanthin, is counted among the xanthophylls, which, in comparison to carotenes such as alpha-carotene, beta-carotene and lycopene, contain, in addition to carbon and hydrogen, functional oxygen groups – in the form of 2 hydroxy (OH) groups in the case of lutein. Structural feature of lutein is polyunsaturated polyene structure (organic compound with multiple carbon-carbon (C-C) double bonds) consisting of 8 isoprenoid units and 11 double bonds, 10 of which are conjugated (multiple consecutive double bonds separated by exactly one single bond). An oxygen-substituted trimethylcyclohexene ring (1 alpha, 1 beta ionone 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 lutein, which are directly related to their biological effects. Despite the polar OH group on the alpha and beta ionone ring, lutein is markedly lipophilic (fat soluble), which influences intestinal absorption (uptake via the intestine) and distribution in the organism. Lutein can occur in different geometric forms (cis/trans isomers) that are convertible into each other:
- All-trans-(3R, 3’R, 6’R)-lutein.
- 9-cis-lutein
- 9′-cis-lutein
- 13-cis-lutein
- 13′-cis-lutein
In plants, the dicyclic xanthophyll exists predominantly (~ 98%) as a stable all-trans isomer. In the human organism, sometimes different isomeric forms can co-occur. Exogenous influences, such as heat and light, can change the configuration of lutein from food. The cis-isomers of lutein, in contrast to the all-trans isomers, exhibit better solubility, higher absorption rates, 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. Because both ring systems of lutein 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. The production of carotenoids in nature is estimated to be about 108 tons per year, most of which is accounted for by the 4 main carotenoids lutein, fucoxanthin – in algae -, violaxanthin and neoxanthin – in plants. Finally, carotenoids, mainly xanthophylls, have been detected in all leaf parts studied so far, especially those with dicyclic structure and hydroxy substituents at C-3 or C-3′ position. Since lutein, in particular, occurs in free as well as esterified forms in numerous plant species and genera, it is probably the most important carotenoid for the functionality of plant organisms.The biosynthesis of lutein occurs from alpha-carotene by hydroxylation of both ionone rings by specific hydroxylases – enzymatic introduction of OH groups. In the cells of the plant organism, lutein 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 – it provides protection against photooxidative damage in the chloroplasts of plant leaves as a component of light-gathering complexes.Antioxidant protection is achieved by so-called quenching (detoxification, inactivation) of reactive oxygen compounds (1O2, singlet oxygen), whereby lutein directly absorbs (takes up) radiation energy via the triplet state and deactivates it via heat release. Since the ability to quench increases with the number of double bonds, lutein with its 11 double bonds has a high quenching activity. In the autumn months, chlorophyll (green plant pigment) is the main substance degraded in chloroplasts, in addition to neoxanthin and beta-carotene. In contrast, the amount of lutein does not decrease. This is the reason why plant leaves lose their green color in autumn and the yellow of lutein becomes visible. Lutein is widespread in nature and, along with alpha- and beta-carotene, beta-cryptoxanthin, lycopene as well as zeaxanthin, it is the most abundant carotenoid in plant foods. It is always accompanied by zeaxanthin and is found with it predominantly in dark green leafy vegetables, such as kale, spinach, turnip greens, and parsley, although the content can vary greatly depending on variety, season, maturity, growth, harvesting, and storage conditions, and in different parts of the plant. For example, the outer leaves of cabbage contain 150 times more lutein than the inner leaves. Lutein 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, lutein is responsible for the yellow color of the thighs and claws of chickens, geese and ducks. The color of the egg yolk is also due to the presence of xanthophylls, especially lutein and zeaxanthin – in a ratio of about 4:1. Lutein accounts for about 70% in the egg yolk. In particular, the eggs of chickens, ducks, and canaries contain abundant lutein. According to Chung et al (2004), the bioavailability of xanthophyll from lutein-rich chicken eggs is significantly higher than from plant foods, such as spinach, or lutein supplements. Industrially, dicyclic xanthophyll is obtained by extracting lutein-rich plant parts, especially from the petals of Tagetes (marigold, herbaceous plant with lemon-yellow to brown-red inflorescences). Using genetic engineering methods, it is possible to influence the content and pattern of carotenoids in plants and thus selectively increase the concentration of lutein. Lutein extracted from plants is used both as a food colorant (E161b), including for coloring non-carbonated beverages, energy bars and dietary foods, and as a feed additive to provide coloration in animal products. For example, lutein is added to chicken feed to intensify the color of egg yolks.
Absorption
Because of its lipophilic (fat-soluble) nature, lutein 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 esterified lutein. After release from the dietary matrix, lutein 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 lutein from plant foods varies widely intra- and interindividually, ranging from 30% to 60%, depending on the proportion of fats consumed at the same time. In terms of their promoting influence on lutein absorption, saturated fatty acids are far more effective than polyunsaturated 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 and thus decrease 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 lutein
- PFS, especially omega-3 fatty acids, inhibit lipoprotein synthesis.
In addition to fat intake, lutein bioavailability is also dependent on the following endogenous and exogenous factors [4, 8, 14, 15, 19, 26, 30, 43, 49-51, 55, 63, 66]:
- Amount of lutein supplied alimentarily (with food) – as the dose increases, the relative bioavailability of the carotenoid decreases
- Isomeric form – lutein, 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 lutein
- Food source
- From supplements (isolated lutein in oily solution – free present or esterified with fatty acids), the carotenoid is more available than from plant foods (native, complex-bound lutein), as evidenced by a significantly higher increase in serum lutein levels after ingestion of supplements compared with intake of equal amounts from fruits and vegetables
- From animal foods, for example eggs, the absorption rate of xanthophyll is significantly higher than from foods of plant origin, such as spinach, or lutein supplements
- Food matrix in which lutein is incorporated – from processed vegetables (mechanical comminution, heat treatment, homogenization) lutein is significantly better absorbed (> 15%) than from raw foods (< 3%), because the carotenoid in raw vegetables is crystalline in the cell and is enclosed in a solid cellulose and/or protein matrix, which is difficult to absorb; Since lutein is heat sensitive, foods containing lutein should be prepared gently to minimize losses.
- Interactions with other food ingredients:
- Dietary fiber, such as pectins from fruits, decreases the bioavailability of lutein 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 the body’s lipases (fat-cleaving enzymes) due to steric hindrance and is excreted unchanged) reduces lutein 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 interfere with the intestinal (gut-related) absorption of lutein; thus, the regular use of phytosterol-containing spreads, such as margarine, can lead to a moderately decreased (by 10-20%) serum carotenoid level; by simultaneously increasing the daily intake of carotenoid-rich fruits and vegetables, a reduction in serum carotenoid concentration can be prevented by the consumption of phytosterol-containing margarine
- Intake of carotenoid mixtures, such as lutein, beta-carotene, cryptoxanthin, and lycopene, can both inhibit and promote intestinal lutein uptake-at the level of incorporation into mixed micelles in the intestinal lumen, enterocytes (small intestinal cells) during intracellular transport, and incorporation into lipoproteins-with strong interindividual differences; thus, administration of high doses of beta-carotene (12-30 mg/d) results in increased lutein absorption and serum lutein levels in some subjects, whereas such administration in other subjects is associated with decreased lutein absorption and serum lutein levels-presumably due to kinetic displacement processes along the intestinal mucosa.
- Proteins and vitamin E increase lutein 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 lutein, respectively, which increases carotenoid bioavailability; 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, lutein 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. Chylomicrons are introduced 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, which leads to more efficient uptake of lutein 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 (FFS) and small amounts of lutein into various tissues, for example muscle, adipose tissue and mammary gland, by lipid cleavage. However, the majority of lutein 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 – constriction of CM-R-containing vesicles (cell organelles) into the cell interior). In the liver cells, lutein is partially 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, lipids are cleaved by action of LPL and the lipophilic substances released, including lutein, 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). Lutein 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 lutein 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, zeaxanthin, alpha- and beta-carotene, lycopene as well as alpha- and beta-cryptoxanthin are the main carotenoids in the organism and contribute about 80 % to the total carotenoid content.Lutein is found in all tissues and organs of humans, although there are significant differences in concentration. In addition to the liver, adrenal glands, testes (testicles) and ovaries (ovaries) – especially the corpus luteum (corpus luteum) – the yellow spot of the eye (lat. : macula lutea, the area of the retina (retina) with the greatest density of photoreceptors (“the point of sharpest vision”) in particular has a high content of lutein. The yellow spot is located in the center of the retina temporal (sleep side) of the optic nerve papilla and has a diameter of 3-5 mm. The photoreceptors of the macula lutea are mainly the cones responsible for color perception. The macula contains lutein and zeaxanthin as the only carotenoids, which is why lutein, in interaction with zeaxanthin, is essential (vital) in the visual process. Both xanthophylls can absorb blue (high-energy short-wavelength) light with high efficiency and thus protect retinal cells from photooxidative damage, which plays a role in the pathogenesis (development) of senile (age-related) macular degeneration (AMD). AMD is characterized by a gradual loss of retinal cell function and is the leading cause of blindness in people aged >50 years in industrialized countries. 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 a reduced risk of developing AMD [19, 26, 32, 33, 36, 37, 53, 55-58]. In addition, there is evidence that daily supplementation with lutein (10 mg/day) – alone or in combination with antioxidants, vitamins, and minerals – can improve visual function (visual acuity and contrast sensitivity) in patients with atrophic AMD. Furthermore, Dagnelie et al (2000) found an improvement in mean visual acuity and mean visual field in patients with retinitis pigmentosa and other retinal degenerations (genetic or spontaneous mutation-induced gradual loss of retinal tissue function in which photoreceptors in particular perish) by taking lutein (40 mg/day).In addition to the macula lutea, lutein and zeaxanthin are also found in the crystalline lens as the only carotenoids. By protecting the lens proteins from photooxidative damage, the dicyclic xanthophylls may prevent or slow the progression (progression) of cataract (cataract, clouding of the lens of the eye) [17, 19-21, 26, 31, 53, 55]. This is supported by several prospective studies in which increased intake of lutein- and zeaxanthin-rich foods, such as spinach, kale, and broccoli, reduced the likelihood of developing a cataract or requiring cataract extraction (surgical procedure in which the clouded lens of the eye is removed and replaced with an artificial lens) by 18-50%. In terms of absolute concentration and tissue contribution to total body weight, lutein is mostly localized in adipose tissue (circa 65%) and liver. In addition, lutein 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, lutein is released from tissue depots only very slowly over several weeks after cessation of intake. In the blood, lutein is transported by lipoproteins, which are 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. The carotenoid is present in 75 % of the blood. Carotenoid is 75-80% bound to LDL, 10-25% bound to HDL, and 5-10% bound to VLDL. In a normal mixed diet, serum lutein concentrations range from 129-628 µg/l (0.1-1.23 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 lutein could confirm that large interindividual variations occur with respect to serum lutein concentration.In human serum and breast milk, 34 of the approximately 700 known carotenoids, including 13 geometric all-trans isomers, have been identified to date. Among these, lutein, cryptoxanthin, zeaxanthin, alpha- and beta-carotene, and lycopene have been detected most frequently.
Excretion
Unabsorbed lutein leaves the body in the feces (stool), whereas its metabolites (breakdown products) 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 lutein are hydroxylated (insertion of an OH group) by the cytochrome P-450 system to increase solubility
- 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 lutein 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.
