2.1. Chemical Structure

Lycopene (ψ,ψ-carotene) is a carotenoid characterized by an acyclic (possessing no closed chain) and unsaturated structure, without the presence of a β-ionone ring [36]. It is an isoprene-derived compound with the molecular formula C₄₀H₅₆ (89.45% carbon and 10.51% hydrogen) and a molecular weight of 536.85 g/mol, with a total of 13 carbon-carbon double bonds, equivalent to 11 conjugated and 2 unconjugated [37]. This system forms a cloud of π electrons extending along the polyene chain, which facilitates light absorption in the visible region with peaks at 444, 470, and 502 nm [3]. Similarly, the arrangement of double bonds along the chain gives lycopene the biological functionality of absorbing light in the visible range and acting as a free radical scavenger [38]. In addition, the chemical structure of lycopene is vitally important to health as it is associated with its potential to mitigate radicals, thus preventing oxidative damage in the body, while in the industrial sector, the structure provides the versatility to be used in various processes.

2.2. Properties

Lycopene has antioxidant capacity, captures or scavenges free radicals, and quenches singlet oxygen, which reduces damage caused by oxidative stress at the cellular level. From this, lies the importance of lycopene, given that several investigations have linked oxidative stress as a phenomenon that contributes to the pathogenesis and pathophysiology of many chronic health problems. The antioxidant activity of lycopene comes from its electron-rich environment, which allows it to absorb long wavelengths and neutralize singlet oxygen. According to several studies, these properties give it a greater capacity to eliminate free radicals: twice that of β-carotene and ten times that of α-tocopherol [Figure 1] [12,28,39]. However, this molecule exhibits extremely high lipophilicity (log P, partition coefficient = 15.09–17.64) [37], which limits its potential pharmacological applications. In addition to its low solubility, this molecule is unstable when exposed to light and heat, which poses a fundamental challenge as it can lead to significant degradation during processing. These limitations result in reduced lycopene yield and quality. In this regard, new studies should be conducted to minimize these losses and maximize their benefits in the food, cosmetics, and industrial sectors.

Figure 1: Potential antioxidant capacity of lycopene. Figure our own, created using Microsoft Office PowerPoint (Microsoft Corporation, Redmond, Washington, USA). [Click here to view]

2.3. Lycopene Isomers

Of the 2048 theoretical geometric configurations of lycopene, only 72 cis isomers (5-cis, 9-cis, 13-cis, and 15-cis) show favorable structural stability [Figure 2] [12,28]. It should be noted that during food processing, the use of organic solvents, heat treatments, and catalysts causes lycopene to undergo geometric isomerization, increasing cis-isomers. However, during food storage, this molecule undergoes retro-isomerization, meaning that the ratio of isomers in the final product is variable. This is vital because lycopene isomerization can be directed to maintain its stability, solubility, and bioaccessibility in food.

Figure 2: Chemical structure of various lycopene isomers. Figure our own, created using Adobe Illustrator (Adobe, Inc., San Jose, CA, USA). [Click here to view]

Lycopene is predominantly found in its trans-form because it is more thermodynamically stable than its cis-isomers. An example is the tomato, which is one of the most common sources of lycopene, where the natural trans-configuration exists, and the presence of cis-lycopene can probably be derived as a result of the storage process or treatment of the material [2,3]. The cis-isomers show higher bioavailability owing to their lower aggregation and better solubility in bile micelles, whereas the trans-isomers crystallize easily, which limits their absorption [2,3]. Both cis- and trans-isomers can be synthesized naturally through plants or by microbial fermentation [28]. In this sense, the form in which lycopene is present provides specific characteristics and properties that are potentially useful, as described below.

The bioavailability and antioxidant properties of lycopene are influenced by the presence of geometric isomers and the position of isomerization; Z-isomers have higher antioxidant activity and bioavailability than (all-E)-lycopene. The ratio of lycopene isomerization affects its biological properties. Wang et al. [40] evaluated lycopene samples containing 5%, 30%, and 55% Z-isomers, and found that the 55% total Z ratio of lycopene revealed the highest radical (2,2-diphenyl-1-picrylhydrazyl) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging activity. This indicates that the Z-isomers of lycopene, rather than the isomer (all-E), have a greater health impact; however, Z-isomers are less stable. However, as mentioned above, this response varies depending on how the raw material is processed. However, factors such as the intensity of light incident on the fruit or heat and oxidation during fruit processing can modify the isomeric pattern of lycopene, altering its final composition. It is important to note that some inconsistencies in isomerization data may lead to biases in terms of their actual impact on health, whether in terms of stability and/or antioxidant capacity. Regardless of the isomer, the main sources of lycopene are fruits, vegetables, and processed foods.

4.1. Lycopene Behavior in Response to Environment

4.1.1. Light/radiation

Radiation is a determining factor in lycopene content and biosynthesis, and is modulated by phytochrome-interacting factor (PIF) transcription factors. During the development of the immature green fruit until its final mature green size, PIF transcripts remained constant, but in the orange phase, they doubled, and in the mature red fruit stage, they increased 5 times more [83]. The same authors pointed out that ripe red fruits exposed to light have higher lycopene and β-carotene content than ripe green fruits that contain higher chlorophylls.

PIF regulates carotenoid gene expression in light environments (direct and/or diffuse) and at various temperatures. Curiously, in tomatoes, as the fruits ripen, the light reaching the green fruit flesh creates a self-shading microenvironment that induces high levels of PIF1a and phytochrome Pr in its inactive form (repressing the carotenoid catalytic PSY1 gene). Upon the initiation of the maturation development program, exocarp chlorophyll is degraded, minimizing self-shading, and phytochrome Pr is converted to its active form, Pfr, by photoreversibility. This change causes the PIF1a proteins in the pulp to be degraded, allowing the synthesis of lycopene (by PSY1 expression), which is perceived as a signal that censors the pigment profile, allowing the coordination of color transition and carotenoid accumulation [84].

In this context, tomatoes exposed to intra-canopy light-emitting diode (LED) light significantly increase in lycopene content which may be due to the fact that lycopene accumulation responds to the red/far red ratio by phytochrome signaling, in that sense intra-canopy irradiance with LED may be a technique to increase lycopene by modifying the expression of PSY gene and its isoforms PSY, PSY1, and PSY3 [85].

Similarly, in Capsicum cultivars, lycopene content and accumulation respond strongly to the light environments to which the plant and fruit are exposed, altering the differential expression of genes associated with carotene synthesis [86,87]. In contrast, in open- and net-grown mandarin fruits, lycopene content was between 0.321 and 0.343 mg·100/g, respectively. These responses may be due to modifications in the PSY, carotenoid cleavage dioxygenase 4, and ZEP genes [52]. As a post-harvest treatment, irradiation of green fruit in phase 1 with red light (12 h/day for 15 days and stored in darkness for an additional 6 days or irradiated continuously with red light for 21 days) causes changes in the outer layer of the tomato fruit [88]. The lycopene content in plants is strongly altered (besides variety, cultivar origin, and nutritional management) by interaction with the environment and stressors (abiotic and biotic), such as high/low light intensity, salinity, water deficit, metalloids, and nutrient deficit [Figure 3].

Figure 3: Lycopene – environment interaction and strategies to promote its content in plants. Environmental conditions can cause an increase or an oxidative burst of ROS, which is accompanied by an increase in cytosolic Ca2+, inducing signaling at the cellular level that (i) alters lycopene biosynthesis in leaves and fruits by promoting an increased synthesis of chlorophylls, plastoquinones, phyloquinones, tocopherols, or gibberellins, or (ii) causes cyclization of lycopene to generate molecules such as β-carotene, lutein, zeaxanthin, abscisic acid, and strigolactones. Likewise, lycopene responds to the ripening process of the fruit; therefore, during this stage, lycopene content can be strongly affected by agronomic management conditions and environmental stresses. Alterations in lycopene content are a function of the genetic load of the plant as well as the type, timing, duration, and intensity of environmental stressors. In this situation, a series of strategies can alleviate the damage or promote a greater accumulation of lycopene in the fruit, such as mineral nutrition, rootstocks, biostimulation (proteins, chitosan, microorganisms, and nanomaterials), and the use of hybrid varieties with a greater capacity for carotene synthesis. Figure our own, created using Microsoft Office PowerPoint (Microsoft Corporation, Redmond, Washington, USA). [Click here to view]

4.2. Strategies to Increase Lycopene Content in Crops

5.1. Lycopene’s Bioaccessibility

As an antioxidant biomolecule, lycopene can enter the human diet via fresh or processed foods. However, only a fraction of the food component is released from the solid food matrix and remains available for absorption in the gastrointestinal tract. Bioaccessibility is influenced by factors such as food-processing methods, cooking techniques, diet composition, chewing, isomeric configurations of lycopene, and interactions with probiotics [114].

Food processing plays a crucial role in enhancing lycopene bioaccessibility. By altering the cell walls and weakening the binding forces between lycopene and the tissue matrix, processing methods increase the availability of lycopene for absorption; in tomato juice fermented with Saccharomyces cerevisiae ATCC 9763 the bioaccessibility of lycopene was 45.1 mg·100/g FW due to the disorganization and hydrolyzation of cell walls as well as by a lower pectin content and higher formation of mixed micelles [115]. Consequently, lycopene bioaccessibility is lowest in raw foods, moderately improved in lightly processed foods, and reaches its maximum in thermally processed foods and purified oil preparations. However, the benefits of this processing can be offset by improper storage and handling. Therefore, the quality and quantity of lycopene in food may affect its absorption levels, as well as the metabolism rate during its ingestion.

Unfortunately, processing methods that promote bioavailability can impact and/or alter the structure and content of lycopene, requiring in-depth studies and standardized methods that minimize loss or improve the efficiency of its total content in the food matrix. Thus, new technologies such as the use of Pickering emulsions, micelles, liposomes, bigels, pearls, microcapsules, nanoparticles, and electrospinning [12], as well as the use of technologies such as hot–melt extrusion [116], high-pressure homogenization [117], in combination with additives such as olive or corn oil, digestible lipids, whey protein isolate, and sodium alginate [118,119] can stabilize the molecule by preventing its degradation.

5.2. Lycopene’s Absorption, Bioavailability, and Metabolism

5.2.1. Bioavailability

Lycopene is absorbed similarly to lipids [3,37] orally, gastric and intestinal phases [Figure 4] through the processes of (i) release, (ii) emulsification, (iii) micellar, and (iv) transport [12].

Figure 4: Lycopene digestion scheme. Adapted from Wu et al. [12]. Created using Adobe Illustrator (Adobe, Inc., San Jose, CA, USA). [Click here to view]

5.3. Lycopene in Human Body Systems

Scientific evidence suggests that lycopene plays a positive role in human health by promoting protection in different body systems [Figure 5]. At the cardiovascular level, it decreases oxidative stress owing to its antioxidant and anti-inflammatory effects [13]. Similarly, lycopene presents a potential mechanism for inhibiting lipoprotein oxidation by improving endothelial function and reducing systemic inflammation. These effects contribute to the prevention of atherosclerosis and, thus, the risk of cardiovascular problems [14].

Figure 5: Probable mechanisms of action of lycopene on human health. Figure our own, created using Microsoft Office PowerPoint (Microsoft Corporation, Redmond, Washington, USA). [Click here to view]

Owing to its antioxidant properties, lycopene reduces oxidative stress and prevents immune-cell damage. In this environment, there is positive modulation of the immune system that improves the activity of T lymphocytes and other immune cells, allowing a greater defense capacity of the body in situations of infection or inflammation [15]. In contrast, lycopene seems to be involved in the endocrine system by regulating the hormonal load (estrogens) to improve reproductive health, which could contribute to the prevention of hormonal cancers, such as breast cancer. Similarly, several studies have associated lycopene with a molecule that participates in the prevention of prostate cancer owing to its protective effect against DNA mutations in prostate cells and abnormal cell proliferation [16,123].

Some studies have associated lycopene consumption with protection of the digestive system by reducing inflammation in the gastrointestinal tract and preventing gastric ulcers, which may be because lycopene protects the cells of the stomach lining from oxidative damage. Similarly, its antioxidant properties may help prevent gastrointestinal cancer, particularly colorectal cancer, by reducing the formation of carcinogenic compounds [17].

In the nervous system, lycopene exerts neuroprotective effects by preventing neuronal damage (owing to its antioxidant capacity), protecting brain cells against oxidative stress, the main factor associated with brain aging, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. It is also reported that lycopene can improve cognitive functions by attenuating age-related mental decline [18,124]. Lycopene promotes positive impacts on the skin. As an organ constantly exposed to solar radiation and ultraviolet (UV) rays, the skin is prone to accumulating free radicals responsible for premature aging and skin cancer, and acts as an antioxidant that attenuates and/or eliminates excess radicals, as well as improves elasticity and hydration [125].

Finally, some studies have suggested that lycopene may have protective effects on the respiratory system by reducing lung inflammation, which is beneficial in chronic respiratory diseases, such as asthma and Chronic Obstructive Pulmonary Disease. Studies have also suggested that lycopene protects the lungs from damage caused by pollutants and environmental toxins [19,126].

Although there is a gap in knowledge regarding the ideal doses of lycopene for human consumption, several studies offer a rough estimate of between 2.0 and 20.0 mg/day. These values would require specific knowledge of lycopene intake and selection of the food matrix with the highest bioavailability [37,127]. Therefore, it would be advisable to consume foods with a high lycopene content, such as tomatoes and peppers (and their derivatives), as well as taking supplements.

The intake and use of lycopene are important for health because of its beneficial properties against some specific diseases, such as its ability to reduce LDL cholesterol levels and increase high-density lipoprotein cholesterol levels [128]. In addition, it is believed to contribute to the improvement of endothelial function by promoting vessel dilation and efficient blood circulation [129]. It is also reported to have a protective effect against plaque formation in arteries, minimizing the risk of cardiovascular diseases, such as heart attacks and strokes [13], which are common in today’s societies.

It is also associated with the prevention of bone diseases such as osteoporosis by reducing oxidative stress in the bone and promoting the activity of osteoblastic cells, which are responsible for bone formation [130,131].

Overall, scientific evidence suggests that daily dietary lycopene intake could be an effective strategy to (i) improve human health and (ii) mitigate damage caused by lifestyle stress [15]. However, further studies are required to generalize and refine these findings, and it is likely that the potential impact of this biomolecule may also be affected by its interactions with nutrients and other biocompounds.

Here we show the favorable responses to lycopene consumption; however, factors such as bioavailability (e.g., due to the instability of lycopene isomers as a result of temperature), dosage, form of application, duration of treatment, and individual dietary patterns may generate contradictions in the results. Likewise, some methodological limitations, such as the restricted number of individuals, the absence of matched control groups, and the use of unvalidated instruments, could provide masked, contradictory, or less conclusive data. In this regard, there is a significant knowledge gap that prevents the establishment and validation of permissible lycopene intake limits that promote real benefits in each body system based on individuals’ lifestyles and metabolism, and therefore, further studies are required.

5.4. Lycopene-nutrients-bioactive Compounds Interactions

The interaction of lycopene with various nutrients and bioactive compounds may influence its absorption and potential effects on human health [12]. In human studies, synergism between lycopene and Vitamins C, E, and A, as well as xanthophylls and flavonoids, has been reported. This synergy enhances ROS neutralization and reduces oxidative stress and cell damage. In vegetables such as tomatoes, in addition to lycopene, compounds such as ascorbic acid, tocopherol, and β-carotene are found, which together form a complex network that can help reduce inflammation, delay aging processes, protect against degenerative diseases, contribute to the prevention of chronic diseases, and improve endothelial function, which could reduce the risk of heart disease, probably by mitigating the damaging oxidative effects of ROS. Surprisingly, the bioavailability and efficacy of lycopene improve when consumed with other antioxidants, as the combination seems to protect this biomolecule [38,48].

A fundamental factor in the interaction of lycopene with human health is the food matrix, in which the bioactive compound is included, since it has been demonstrated that the absorption process of this metabolite is directly influenced by this and its association with other nutrients. The isomerization of lycopene can also facilitate its absorption; however, it can be affected by factors such as the presence of oil, gastric pH, and the intestinal digestion process. For example, edible vegetable oils (peanut, olive, soybean, and canola) can enhance isomerization and lycopene absorption [26,132]. For example, incorporating dietary fats such as olive pomace oil and corn oil induces greater bioaccessibility of lycopene by 28.1% and 8.1% [119], so these oils may be recommended for use as additives in food matrices.

Carotenoids and minerals are another group of compounds that interact with lycopene. Simultaneous intake of lycopene with other carotenoids, such as lutein and β-carotene, can alter the amount of lycopene absorbed in the intestine [27,133]. Therefore, the consumption of a diet rich in fruits and vegetables that provides lycopene and other bioactive compounds could be associated with lower morbidity and mortality and greater longevity, partially because of the potential effect of lycopene [13,134]. This response may be due to the protective effect of lycopene against the radical molecules associated with cell damage.

5.5. Lycopene-free Radical Interactions

As a carotenoid with a highly conjugated chemical structure, lycopene has potent antioxidant capacity [Table 2]. Its interaction with free radicals is primarily determined by free radical scavenging. In this context, lycopene acts as a scavenger of ROS and RNS because of its multiple conjugated double bonds that allow it to donate electrons to hydroxyl radicals, superoxide, and lipid peroxides, as well as singlet oxygen (⁺O₂) to neutralize them and prevent cell damage [21,135] by reducing or inhibiting lipid peroxidation, which protects cell membranes and LDL [22]. The impact on functional antioxidant activity in vivo may be due to the fact that (i) the amount of lycopene ingested can maximize or minimize its efficiency (depending on fat or fiber consumption, respectively), (ii) the processing method affects the lycopene content of the food matrix, and/or (iii) the alteration in the isomers present.

Table 2: The main health impact of lycopene.

Lycopene also modulates oxidative stress by regulating the expression of antioxidant genes such as superoxide dismutase, catalase (CAT), and glutathione peroxidase (GPx) that minimize the amount of free radicals in the body [23]. Similarly, lycopene inhibits the activation of nuclear factor kappa B, a key regulator of inflammatory response and oxidative stress. By modulating this pathway, lycopene contributes to the reduction of inflammatory processes and the maintenance of cellular homeostasis; that is, it promotes the silencing of proinflammatory genes and promotes apoptosis in cancer cells [20]. It also inhibits insulin-like growth factor 1 (IGF-1) binding to its receptor by increasing IGF-binding protein-1 concentrations, interfering with IGF-1 signaling, and reducing the activation of the phosphatidylinositol 3-kinase and RAS-mitogen-activated protein kinase pathways that limit cell proliferation and promote apoptosis [138].

In prostate cancer cells, lycopene decreases the expression of androgen receptors and modulates the nuclear localization of β-catenin, thereby reducing cell proliferation and cell cycle progression. Likewise, lycopene is associated with the activation of the peroxisome proliferator-activated receptor gamma-activated receptor [127,139], liver X receptor alpha, and ABCA1 transporter pathway, promoting a reduction in cholesterol concentration in prostate cancer cells, thereby reducing their proliferation [137]. These mechanisms highlight the potential of lycopene in the prevention and treatment of diseases such as cancer, especially prostate cancer, and underline the importance of its inclusion in the diet for health promotion. However, the capacity of lycopene can be altered by handling and processing fruits and vegetables during food processing or by the conditions used for its extraction and industrial use.

6.1. Epidemiological Evidence

Lycopene-rich diets have been associated with a reduced risk of chronic diseases, particularly those related to aging [140]. As mentioned above, this may be due, in part, to its high antioxidant and anti-inflammatory capacity. However, caution should be exercised in this interpretation, as lifestyle, diet, and metabolism can have a positive or negative impact on this response.

6.2. Clinical Trials

Currently, 773 clinical trials are registered in the Cochrane Library, an international network dedicated to producing systematic reviews that support informed health decisions. These trials focus on a wide range of conditions, from general health maintenance to specific diseases, such as prostate cancer, infertility, periodontitis, and cellulitis, as well as investigations into lycopene pharmacokinetics. However, a significant portion of these trials did not publish their results [145].

In a multicenter, randomized, double-blind, phase II pilot study in patients with metastatic colorectal cancer treated with panitumumab, it was found that the administration of lactolycopene (20 mg·100/g of food/matrix) induced a reduction in grade 2–3 panitumumab skin toxicity in 41% of the patients, which was due to the reduction in malondialdehyde production, as well as by the replenishment of antioxidant consumption, a response mediated by the hydrophobic property of lactolycopene itself, which showed an increase in the plasma of the patients [146] [Figure 6]. Therefore, studies have been conducted to define their safety and possible toxicological impacts, which are discussed in the following section.

Figure 6: Potential response to lycopene use in humans in clinical trials. Figure our own, created using Microsoft Office PowerPoint (Microsoft Corporation, Redmond, Washington, USA). [Click here to view]

Furthermore, the design of clinical trials (i.e., age cohort, lycopene dosage and sources, and duration) may yield contradictory data due to diversity in human metabolism and lycopene itself. Therefore, future studies should consider a nutritional “stabilization” phase that minimizes noise derived from dietary habits and maximizes the potential of lycopene. Similarly, clinical trials may choose to develop specific cohorts of children, young adults, middle-aged adults, and the elderly, as well as comprehensive approaches to the main pathophysiologies. We suggest conducting studies (meta-analyses) that include, in addition to the bioavailability of lycopene, clinical assessment parameters to clarify which variables respond most or best to interventions with this antioxidant.

Overall, the data show a positive impact between lycopene consumption and the reduction of certain specific diseases. However, this causal response must be interpreted holistically and consider parameters such as actual lycopene intake, bioavailability (which, as mentioned above, involves a knowledge gap in itself), time of intake, and the consumption of lycopene “enhancers” (fatty acids) or “limiters” (fiber). We believe that the human-environment-lifestyle (epigenome) interaction may be a parameter that epidemiological studies and clinical trials should strongly consider as a determinant of the favorable response to lycopene, since this interaction may influence how lycopene promotes health.

6.3. Safety and Toxicological Considerations

Lycopene has been extensively studied for its safety as a food additive and dietary supplement. It is currently authorized as a food additive (color) in the European Union under Annex II of Regulation (EC) No 1333/2008, allowing its use in several food categories. The Scientific Panel on food additives, flavorings, processing aids, and materials in contact with food (AFC) evaluated its toxicological data and established an acceptable daily intake (ADI) of 0.5 mg/kg body weight per day, applying a safety factor of 100 [147]; this value corresponds to a combined uncertainty factor (uncertainty factor of 10 times × factor of 10 times relating to interindividual variability in humans) that considers subpopulations at higher risk due to certain factors such as nutritional status, medication use, diet, pregnancy status, and other pathophysiology.

However, safety concerns have been raised due to the possibility that the highest estimated intakes for both children and adults may exceed the established ADI of 0.5 mg/kg body weight [148]. Despite these concerns, most notifications submitted by companies to the European Chemicals Agency through CLP notifications indicate that lycopene is not hazardous [149]. Reproductive and teratological studies support the safety of lycopene. In a teratology study in Wistar rats, lycopene formulations showed no maternal toxicity or teratogenic effect. The only observation was a slight increase in the incidence of extra-thoracic ribs in the treated groups compared with the controls, with no other relevant changes [23].

Several studies have evaluated the safety and toxicity of lycopene and concluded that its extract from natural tomato oleoresin is safe for human consumption. For instance, a no-observed-adverse-effect level of 4500 mg/kg/day was established, which significantly exceeded the typical dietary intake with no significant toxicity reported in previous studies [150]. In addition, tomato oleoresin rich in lycopene Z-isomers (10.9% lycopene, with 66.3% Z-isomer content) demonstrated no mutagenic potential or adverse effects in toxicity tests, including an LD₅₀ >5000 mg/kg body weight in rats [151].

Biddle et al. [152] report that intervention with a daily intake of 29.4 mg of lycopene (through a 330 mL serving of 100% vegetable juice V8 for 30 days) in participants with heart failure promoted plasma lycopene levels up to 0.76 μmol/L, making it safe for consumption. Similarly, consumption of 11 mg of lycopene per day (raw tomatoes at breakfast and lunch) for 8 weeks in overweight postmenopausal women (aged 45–70) with a body mass index >24 kg/m² was not only safe but also showed a significant response in reducing the risks of metabolic syndrome [153].

6.4. Lycopene-drug Interactions

Research suggests that lycopene can enhance the therapeutic effects of certain medications. For example, it has been shown to significantly reduce blood glucose levels in diabetic models when combined with gliclazide without altering its pharmacokinetics [154]. In addition, the antioxidant properties of lycopene may help mitigate the toxic side effects of chemotherapeutic agents, potentially offering protective benefits during cancer treatment [155].

Lycopene’s effects on drug metabolism further highlight the need for caution in certain contexts. It exhibits a mixed inhibition mechanism for ponatinib metabolism in both rat and human liver microsomes, indicating potential interactions in patients with chronic myeloid leukemia [156]. In addition, lycopene has a moderate inhibitory effect on CYP2E1, suggesting that its co-administration with drugs metabolized by this enzyme requires careful monitoring [157].

A pre-clinical study in men with metastatic prostate cancer (phase I trial: NCT0149519) showed that lycopene enhanced the efficacy of docetaxel against prostate cancer when treated with 21-day cycles of 75 mg/m² docetaxel/and androgen deprivation therapy plus lycopene (30, 90, or 150 mg/day). This suggests that the combination has low toxicity and favorable pharmacokinetics [158].

6.5. Recommended Daily Intake

There is an ongoing debate regarding the amount of lycopene needed to achieve its functional benefits, as studies have reported highly variable results, making comparisons and clear recommendations challenging. Discrepancies among epidemiological, in vitro, and in vivo studies, along with lycopene’s lack of provitamin A activity, contribute to it not being classified as an essential nutrient, thus preventing the establishment of an official RDI. However, some suggestions include consuming 7–10 servings of lycopene-rich food, whereas others recommend consuming 5–35 mg/day. The European Food Safety Authority has set an acceptable ADI of 0.5 mg/day. Since the bioavailability of lycopene depends on processing, fat intake, and the isomeric form of the carotenoid, it is recommended to select the appropriate food matrix (fresh or processed, rich in cis-isomers) and accompany lycopene consumption with fats to achieve the RDI. In this context, the sources of lycopene in humans vary, ranging from fruits and vegetables to dyes and additives. The latter is economically important for the food industry.

7.1. Stability and Modification of the Lycopene Content in Food

Owing to its highly unsaturated structure, lycopene is prone to chemical reactions [28] by thermal energy, oxygen, pH, light, and metals, causing a change in its configuration through isomerization [37,38]. Isomerization occurs as a degradation step because cis-isomers are less stable and can cleave more easily than trans-isomers [159]. The stability of lycopene configurations was in the order of all-trans > 9-cis > 13-cis > 15-cis. Lycopene degradation varies depending on fruit and vegetable matrices. For example, lycopene degradation differs widely among tomato peel, puree, and orange matrices [160].

Temperature can accelerate lycopene degradation; in tomatoes crushed at 70°C, 80°C, 90°C, and 100°C for 120 min, lycopene degradation was 23.94%, 30.17%, 45.05%, and 55.24%, respectively [28]. Likewise, the type of fruit extraction (hot air, vacuum drying, and microwave vacuum drying) conditions the degradation of lycopene; the higher the temperature, the greater the degradation, following the first law of degradation kinetics [161]. These data suggest that processing temperature promotes lycopene instability [28].

Light promotes lycopene oxidation, and its isomerization depends on the bond and isomer. Thus, the protection of fruits and vegetables from light could decrease the oxidative degradation and isomerization of lycopene, apparently because cis-isomers are significantly reduced by exposure to light, revealing their instability with respect to all-trans isomers [28].

Considering that the optimal pH range for stabilizing lycopene is 3.5–4.5, probably the alterations in these values may promote cis-bond formation [37]. Similarly, oxygen, which presents an unpaired electron, can cause lycopene degradation because of its high reactivity. Similarly, metal ions (FeCl₃) can induce oxidative degradation by exerting catalytic effects on lycopene Z-isomerization [28]. These changes caused by processing, by altering the proportion of isomers, promote oxidation and degradation of the food matrix, which results in reduced or limited bioavailability of lycopene for humans, mainly due to the alteration of the nature of the molecule.

In this sense, proposals have been made to improve lycopene stability, such as encapsulation systems that, in addition to promoting a physical barrier, exhibit solubility [28]. Among these, emulsions, microemulsions, nanoemulsions, nanostructured lipid carriers, hydrogels, Pickering emulsions, and liposomes are notable [162]. In this context, an emulsion loaded with Z-lycopene using ovalbumin-chitosan complexes showed improved carotenoid stability under UV irradiation [39]. Pickering emulsions stabilized by complexes of whey protein isolate fibrils and sodium alginate offer better protection of lycopene against thermal degradation and light [163]. Thus, food processing had a significant influence on lycopene concentrations in the food matrices [Table 4].

Table 4: Lycopene content according to processing.

In Psidium guajava L., the freeze-drying dehydration method (low temperature and pressure) allows for higher lycopene conservation (7.66 mg·100^–1 dry weight [DW]) compared to hot air and vacuum drying (4.36 mg·100/g DW) [166]. Similar to thermochemical treatment (tomato pulp heated at 80–82°C for 30 min before applying 0.05% potassium metabisulfite, 0.05% sodium metabisulfite, 0.05% potassium sorbate, and 0. 05% sodium benzoate, 0.5% ascorbic acid, and citric acid (1%) promote higher lycopene conservation (4.328–5.987 mg·100/g FW) over 120 days when stored at 30 ± 1°C [167].

Some tomato products, such as sauces and pastes, tend to have a higher lycopene content than fresh tomatoes. Studies report that tomato sauces contain between 9.9 and 13.4 mg·100/g of lycopene, whereas fresh tomato has between 0.88 and 7.74 mg·100/g. It should be noted that dietary sources of lycopene are mainly in the isomeric trans-form [122].

However, the extraction method is crucial for determining the amount of lycopene extracted and recovered [1]. Extraction methods, such as vapor entrainment and organic solvents, showed variations in lycopene extraction efficiency, and solvents such as ethyl acetate showed high lycopene extraction efficiency. Recently, some enzyme-assisted methods from tomato tissues and peels have shown higher yields using cellulases and pectinases, up to 18-fold in lycopene recovery. However, the hexane: acetone:ethanol mixture (50:25:25) optimized the recovery of the compound. Likewise, surfactants have been used to extract lycopene from various sources (watermelon, pink grapefruit, guava, melon, fresh red tomatoes, and papaya) with a recovery of up to 25% lycopene [168]. Taken together, these data suggest a high variability in lycopene content depending on the type of processing and extraction method employed.

As an antioxidant biomolecule, lycopene can enter the human diet through fresh or processed foods; however, in the latter, lycopene content depends on the source, processing, and extraction method. Therefore, consumption of foods rich in lycopene is not necessarily associated with an increase in this antioxidant in humans. To understand and elucidate the benefits of lycopene in humans, in-depth studies have been conducted on animals and humans to understand the impact of this molecule on biology and its potential impact on organisms.

7.2. Lycopene as a Natural Colorant and Antioxidant in the Food Industry

Lycopene offers significant potential as a colorant in various food products due to its vibrant red hue and associated health benefits. As a natural colorant, lycopene aligns with the growing consumer preference for natural ingredients over synthetic alternatives, making it an attractive option for food manufacturers.

7.2.1. Stability and bioavailability

Tomato-based products, such as sauces, pastes, and juices, are the primary sources of lycopene in the diet. The processing of tomatoes enhances the bioaccessibility of lycopene, as heat and mechanical processing break down cell walls and release more lycopene [164]. The antioxidant properties of lycopene are particularly noteworthy, as they help protect food products from oxidative damage, thereby extending shelf life and maintaining quality [1]. This capability is crucial in the food industry, where the preservation of flavor and nutritional value is paramount. Moreover, the effectiveness of lycopene as a colorant is enhanced when consumed along with dietary fats, further increasing its bioavailability and health benefits. Its strong color and non-toxicity make it a suitable alternative to artificial colorants, which are increasingly being scrutinized by health-conscious consumers [Figure 7]. In addition, lycopene stability during processing and storage is a critical factor that supports its use in food products, as it remains effective for extended periods [38].

Figure 7: Main industrial application of lycopene. Figure our own, created with BioRender (biorender.com). [Click here to view]

7.3. Applications in Nutraceuticals and Dietary Supplements

Lycopene has been playing a dual role as a dietary supplement and nutraceutical [Figure 6]. Its properties have been linked to various health benefits, including potential protective effects against chronic diseases.

Its health-promoting properties have been extensively studied owing to its capacity as a nutraceutical. Its antioxidant activity is instrumental in neutralizing free radicals, thereby mitigating oxidative stress, which is a key contributor to various chronic diseases [137]. In addition, lycopene has been associated with cardiovascular benefits such as improved lipid profiles and reduced blood pressure, which may collectively decrease the risk of atherosclerosis and hypertension [2]. Moreover, emerging research indicates that lycopene may play a role in neuroprotection, potentially offering benefits in conditions such as depression by enhancing synaptic plasticity [2].

As a dietary supplement, lycopene is available in various formulations, such as capsules and tablets, aimed at augmenting daily intake, particularly in individuals with insufficient dietary consumption [137]. The bioavailability of lycopene is notably influenced by its formulation and the presence of dietary fats, by improving its absorption up to ~4.4 times more than a fat-free diet [120]. Studies have demonstrated that lycopene incorporated into lipid-based delivery systems such as oil suspensions or emulsions exhibits improved bioavailability. For instance, lycopene dissolved in olive oil (20 mL) has shown higher absorption rates than lycopene dissolved in other media [120]. This enhanced bioavailability is crucial for maximizing the physiological benefits.

7.4. Development of Pharmaceutical and Cosmetic Applications

Lycopene has attracted considerable attention for its pharmaceutical potential due to its strong antioxidant and anti-inflammatory properties. Its ability to neutralize free radicals helps prevent cellular damage and reduces the risk of chronic diseases, making it a promising candidate for various medical applications. Studies have suggested that lycopene may contribute to cardiovascular health by reducing oxidative stress and inflammation, thereby lowering blood pressure and improving lipid profiles, which can mitigate the risk of atherosclerosis, heart attack, and stroke [177]. In cancer prevention, antioxidant activity plays a crucial role in preventing DNA damage and inhibiting tumor growth, with research indicating its potential to induce apoptosis in cancer cells [178]. In addition, the photoprotective effects of lycopene have been explored to reduce UV-induced skin damage and potentially lower the risk of skin cancer. Emerging evidence also highlights its neuroprotective properties, suggesting its benefits in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, as it may reduce oxidative stress and inflammation in the brain [179]. These diverse therapeutic applications underscore the significance of lycopene in pharmaceutical research; however, further studies are required to optimize its bioavailability and therapeutic efficacy.

In the cosmetic industry, lycopene and other carotenoids are highly valued for their skin-protective and anti-aging properties. Lycopene’s potent antioxidant activity helps shield the skin from environmental stressors such as UV radiation and pollution, thereby preventing premature aging. Commonly incorporated into serum, creams, and sunscreens [Figure 6], lycopene contributes to skin rejuvenation and protects against UV-induced damage; for instance, lycopene-infused facial creams are marketed to reduce fine lines and wrinkles while enhancing skin elasticity and overall appearance; mainly by significantly reducing the parameters associated with skin damage (Δa*, MMP-1, ICAM-19) associated with a significant increase in minimum erythema dose, skin thickness, and skin density [35]. Similarly, carotenoids serve as natural colorants, imparting hues from yellow to orange without relying on synthetic additives [180] and combating oxidative stress by strengthening the endogenous antioxidant defenses of the skin, including enzymes such as CAT and GPx, as well as non-enzymatic elements such as L-ascorbic acid and α-tocopherol [34]. Moreover, clinical trials have confirmed their effectiveness in reducing the signs of premature aging, and their ability to absorb UV light and neutralize free radicals (mainly ¹O₂) offers robust photoprotection against sun-induced damage [181].

The data observed reveal that lycopene extraction and handling techniques and methods are a fundamental challenge in the industrial sector and represent a key element that must be implemented and developed to promote greater optimization, efficiency, and effectiveness. However, achieving optimal stability of this molecule on an industrial scale suggests a major challenge involving the concatenation of theoretical knowledge and, perhaps, the development of machines and new methods, for example, using artificial intelligence and/or mathematical algorithms.

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