Lycopene (derived from the scientific name Solanum lycopersicum: “tomato”) belongs to the class of carotenoids – those secondary plant compounds (bioactive substances that do not have a life-sustaining nutritive function but are distinguished by their health-promoting effects – “anutritive ingredients”) that are lipophilic (fat-soluble) pigment dyes responsible for the yellow, orange, and reddish colors of numerous plants. According to their chemical structure, carotenoids can be divided into carotenes, which are composed of carbon (C) and hydrogen (H) – hydrocarbons -, and xanthophylls, which contain oxygen (O) in addition to C and H atoms – substituted hydrocarbons. Lycopene belongs to the carotenes and has the molecular formula C40H56. Similarly, alpha-carotene and beta-carotene represent carotenes, while lutein, zeaxanthin and beta-cryptoxanthin belong to the group of oxygenated xanthophylls. Structural feature of lycopene is the polyunsaturated polyene structure (organic compound with multiple carbon-carbon (C-C) double bonds) consisting of 8 biological isoprenoid units (→ tetraterpene) and 13 double bonds, 11 of which are conjugated (multiple consecutive double bonds separated by exactly one single bond). The system of conjugated double bonds enables lycopene to absorb visible light in the higher wavelength range, which gives carotene its red color. In addition, the polyene structure is responsible for some physicochemical properties of lycopene that are directly related to their biological effects (→ antioxidant potential). Unlike other carotenoids, such as alpha- and beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin, lycopene does not bear a trimethylcyclohexene ring at the ends of the isoprenoid chain (→ acyclic structure). In addition, carotene has no substituents attached. Lycopene is markedly lipophilic (fat-soluble), which affects intestinal (gut-related) absorption and distribution in the organism. Lycopene can occur in different geometric forms (cis-/trans- and Z-/E-isomerism, respectively), which are convertible into each other:
- All-trans-lycopene
- 5-cis-lycopene
- 7-cis-lycopene
- 9-cis-lycopene
- 11-cis-lycopene
- 13-cis-lycopene
- 15-cis-lycopene
In the plant, the all-trans isomer dominates with 79-91%, while in the human organism more than 50% of lycopene is in the cis form. The all-trans lycopene contained in plant foods is partially isomerized (converted) to its cis-forms by exogenous influences, such as heat and light, on the one hand, and by the acidic gastric juice, on the other hand, which have better solubility, higher absorption rate, and faster intracellular and extracellular (inside and outside the cell) transport compared to the all-trans isomers due to lack of aggregation (agglomeration) and crystallization ability. However, in terms of stability, all-trans lycopene outperforms most of its cis isomers (highest stability: 5-cis ≥ all-trans ≥ 9-cis ≥ 13-cis > 15-cis > 7-cis- > 11-cis: lowest stability). Of the approximately 700 carotenoids identified, about 60 are convertible to vitamin A (retinol) by human metabolism and thus possess provitamin A activity. Because of its acyclic structure, lycopene is not one of the provitamins A [4, 6, 22, 28, 54, 56-58].
Synthesis
All-trans lycopene is synthesized (formed) by all plants capable of photosynthesis, algae and bacteria, and fungi. The starting substance for lycopene biosynthesis is mevalonic acid (branched-chain, saturated hydroxy fatty acid; C6H12O4), which is converted to dimethylallyl pyrophosphate (DMAPP; C5H12O7P2) according to the mevalonate pathway (metabolic pathway by which, starting from acetyl-coenzyme A, the biosynthesis of isoprenoids occurs – to build steroids and secondary metabolites) via mevalonate 5-phosphate, mevalonate 5-pyrophosphate and isopentenyl 5-pyrophosphate (IPP). DMAPP condenses with three molecules of its isomer IPP (C5H12O7P2), giving rise to geranylgeranyl pyrophosphate (GGPP; C20H36O7P2). Condensation of two molecules of GGPP leads to the synthesis of phytoene (C40H64), a central substance in carotenoid biosynthesis.As a result of several desaturations (insertion of double bonds, turning a saturated compound into an unsaturated one), phytoene is converted into all-trans lycopene. Lycopene is the starting substance of all other carotenoids. Thus, cyclization (ring closure) of the two terminal isoprene groups of lycopene results in the biosynthesis of beta-carotene, which can be transformed (converted) to the oxygenated xanthophylls by hydroxylation (reaction with elimination of water). In the cells of the plant organism, all-trans-lycopene is localized within membranes, in lipid droplets, or as a crystal in the cytoplasm. In addition, it is incorporated into the chromoplasts (plastids colored orange, yellow, and reddish by carotenoids in petals, fruits, or storage organs (carrots) of plants) and chloroplasts (organelles of cells of green algae and higher plants that perform photosynthesis) – incorporated into a complex matrix of proteins, lipids, and/or carbohydrates. While carotene 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-harvesting complexes. Antioxidant protection is achieved by so-called quenching (detoxification, inactivation) of reactive oxygen compounds (1O2, singlet oxygen), where lycopene 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, lycopene with its 13 double bonds has the highest quenching activity compared to other carotenoids. Compared to lutein, lycopene is much less abundant in plants and animals. The red pigment dye can be detected sporadically in some sponges (Porifera; aquatic animal phylum within the Tissueless), insects, and phototrophic bacteria (bacteria capable of using light as an energy source). Major sources of lycopene are ripe fruits and vegetables, such as tomatoes (0.9-4.2 mg/100 g) and tomato products, red grapefruit (~ 3.4 mg/100 g), guava (~ 5.4 mg/100 g), watermelon (2.3-7.2 mg/100 g), papaya (~ 3.7 mg/100 g), rosehip, and certain olive species, for example, the drupes of the coral oilweed Elaeagnus umbellata. In this context, lycopene contents are subject to considerable variation depending on cultivar, season, ripeness, site, growth, harvest, and storage conditions and can vary greatly in different parts of the plant. In tomatoes and tomato products, lycopene is about 9-fold more concentrated than beta-carotene. About 80-85% of dietary lycopene intake is due to the consumption of tomatoes and tomato products, such as tomato paste, ketchup, tomato sauce, and tomato juice. The strong lipophilicity (fat solubility) of lycopene is the reason that the carotene cannot be dissolved in aqueous environments, causing it to aggregate and crystallize rapidly. Thus, lycopene in fresh tomatoes is present in the crystalline state and is enclosed in a solid cellulose and/or protein matrix that is difficult to absorb. Food processing operations, such as mechanical comminution and thermal treatment, result in the release of lycopene from the food matrix and increase its bioavailability. However, heat exposure should not be too long or too severe, otherwise oxidation, cyclization (ring closure), and/or cis-isomerization of the all-trans lycopene may result in activity losses of more than 30%. For reasons of higher bioavailability and concentration of lycopene, tomato products, such as tomato paste, tomato sauce, ketchup, and tomato juice, have significantly higher lycopene content than fresh tomatoes. For use in the food industry, lycopene is both synthetically produced and extracted from tomato concentrates using organic solvents. It is used as a food colorant (E 160d) and is thus a coloring ingredient in soups, sauces, flavored beverages, desserts, spices, confectionery and baked goods, among others. Furthermore, lycopene is an important precursor of flavorings.It is cleaved by co-oxidation with the help of lipoxygenases, by reacting with reactive oxygen compounds and under thermal stress, resulting in carbonyl compounds with a low odor threshold. These degradation products play an essential role in the processing of tomatoes and tomato products.
Resorption
Due to its pronounced lipophilicity (fat solubility), lycopene 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 for solubilization and micelle formation, and esterases (digestive enzymes) for cleavage of esterified lycopene. After release from the food matrix, lycopene 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 taken up by a passive diffusion process into the enterocytes (cells of the small intestinal epithelium) of the duodenum (duodenum) and jejunum (jejunum). Evidence exists that intestinal absorption of lycopene and other carotenoids involves a specific epithelial transporter that is saturable and whose activity depends on carotenoid concentration. The absorption rate of lycopene from plant foods varies widely intra- and interindividually, ranging from 30% to 60%, depending on the proportion of simultaneously supplied fats [3-5, 22, 50, 54, 57]. In terms of their promoting influence on lycopene 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 lycopene
- PFS, especially omega-3 fatty acids, inhibit lipoprotein synthesis.
Lycopene bioavailability is dependent on the following endogenous and exogenous factors in addition to fat intake [4, 5, 8, 14, 15, 22, 28, 29, 40, 46-48, 54, 62, 63, 68]:
- Amount of lycopene supplied alimentarily (through the diet) – as the dose increases, the relative bioavailability of the carotenoid decreases
- Isomeric form – lycopene, 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 of all-trans to cis-lycopene
- Food source – from supplements (isolated, purified lycopene in oily solution – free present or esterified with fatty acids), the carotenoid is more available than from plant foods (native, complex-bound lycopene), as evidenced by a significantly higher increase in serum lycopene levels after ingestion of supplements compared with ingestion of equal amounts from fruits and vegetables
- Food matrix in which lycopene is incorporated – from tomato products, such as tomato soup and tomato paste, lycopene is absorbed significantly better than from raw tomatoes, because processing (mechanical crushing, heat treatment, etc. ) plant cell structures are broken, the bonds of lycopene to proteins and dietary fiber are cleaved, and crystalline carotenoid aggregates are dissolved; mixing tomato-containing foods with oil further increases the bioavailability of lycopene.
- Interactions with other food ingredients:
- Dietary fiber, such as pectins from fruits, decreases the bioavailability of lycopene by forming poorly soluble complexes with the carotenoid
- Olestra (synthetic fat substitute consisting of esters of sucrose and long-chain fatty acids (→ sucrose polyester) that cannot be cleaved by endogenous lipases (fat-cleaving enzymes) due to steric hindrance and is excreted unchanged) reduces lycopene absorption; according to Koonsvitsky et al (1997) results from a daily intake of 18 g Olestra over a period of 3 weeks a decrease in carotenoid serum levels by 27%; according to Thornquist et al (2000) is already after small intake amounts of Olestra (2 g / day) a decrease in carotenoid serum levels (by 15%) to record.
- 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 lycopene; 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 lycopene, beta-carotene, cryptoxanthin, zeaxanthin, and lutein, can both inhibit and promote intestinal lycopene uptake-at the level of incorporation (uptake) into mixed micelles in the intestinal lumen, enterocyte during intracellular (within-cell) transport, and incorporation into lipoproteins-with strong interindividual differences
- According to Olsen (1994), administration of high pharmacologic doses of beta-carotene results in decreased lycopene absorption and a decrease in serum lycopene levels-presumably due to kinetic displacement processes along the intestinal mucosa; thereby, 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 lycopene, zeaxanthin, and lutein, and are present in serum in significant amounts
- Gaziano et al (1995) demonstrated a decrease in lycopene content in lipoproteins, especially in the LDL (low density lipoproteins; cholesterol-rich low density lipoproteins) fraction, after six days of ingestion of 100 mg of synthetic and natural beta-carotene
- Wahlquist et al (1994) found an increase in serum lycopene concentrations with daily administration of 20 mg beta-carotene for a period of one year
- Gossage et al (2000) supplemented breastfeeding and non-breastfeeding women aged 19-39 years with 30 mg each of beta-carotene for 28 days with the result that serum lycopene concentrations were unaffected, while serum alpha and beta-carotene levels increased and serum lutein levels were significantly decreased
- Individual digestive performance, such as mechanical comminution in the upper digestive tract, gastric pH, bile flow – thorough chewing and low pH of gastric juice promote cell disruption and release of bound and esterified lycopene, 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, lycopene is incorporated into chylomicrons (CM, lipid-rich lipoproteins), 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 (atrium cordis dextrum). Chylomicrons are introduced into the peripheral circulation by the pumping force of the heart. 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 remnant particles) during transport to the liver. In this context, lipoprotein lipase (LPL) plays a crucial role, which is located on the surface of endothelial cells (cells lining the inside of blood vessels) of blood capillaries and leads to the uptake of free fatty acids and small amounts of lycopene into various tissues, for example muscle, adipose tissue and mammary gland, by lipid cleavage. However, the majority of lycopene 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, lycopene is partly stored, and another part is incorporated into VLDL (very low density lipoproteins; lipid-containing lipoproteins of very low density), through which the carotenoid reaches extrahepatic (“outside the liver”) tissues via the blood circulation. As VLDL circulating in the blood binds to peripheral cells, lipids are cleaved by action of LPL and the lipophilic substances released, including lycopene, are internalized (taken up internally) by passive diffusion. This results in the catabolism 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). Lycopene 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 lycopene 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). Lycopene and beta-carotene are the most abundant carotenoids in blood and tissues. While lycopene dominates in the adrenal glands, testes (testicles), prostate, and liver, the lungs and kidneys have approximately equal amounts of lycopene and beta-carotene. Because lycopene is markedly lipophilic (fat soluble), it is also localized in adipose tissue (~1 nmol/g wet weight) and skin, but at lower concentrations than in testes (testes) and adrenals (up to 20 nmol/g wet weight), for example [4, 15, 22, 28, 40, 50, 54, 56-58]. In cells of individual tissues and organs, lycopene is particularly a component of cell membranes and influences their thickness, strength, fluidity, permeability (permeability), as well as effectiveness. Since lycopene has the greatest antioxidant potential compared to other carotenoids and is preferentially stored in prostate tissue, it is considered the factor with the highest effectiveness in terms of prostate cancer prevention. In blood, lycopene 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% to HDL, and 5-10% to VLDL. Depending on dietary habits, serum lycopene concentration is about 0.05-1.05 µmol/l and varies according to sex, age, health status, total body fat mass, and level of alcohol and tobacco consumption. 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 them, in addition to lycopene, the carotenes alpha- and beta-carotene and the xanthophylls lutein, zeaxanthin, and cryptoxanthin, were detected most frequently.
Excretion
Unabsorbed lycopene leaves the body in the feces (stool), whereas intestinally (via the intestine) absorbed lycopene is eliminated in the urine in the form of its metabolites. Endogenous degradation of lycopene occurs by beta-carotene dioxygenase 2 (BCDO2), which cleaves carotene to pseudojonone, geranial, and 2-methyl-2-hepten-6-one. In order to convert the degradation products of lycopene 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 (intermediates) of lycopene are 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 the metabolites with the help of glucuronyltransferase
After a single administration, the retention time of carotenoids in the body is between 5-10 days.
