Re: 리코펜(lycopene)의 효과 - 2019년 리뷰

[문형철]

beyond reason

Lycopene – a bioactive carotenoid offering multiple health benefits

: a review

Sylwia Przybylska

First published: 24 July 2019

https://doi.org/10.1111/ijfs.14260

Citations: 10

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Summary

Lycopene is a natural red tomato pigment whose presence in the diet is beneficial to human health. It is believed to modify the course of chronic conditions, including neoplastic diseases. Clinical research results confirm‎ its protective effects on the cardiovascular system. It lowers the risk of myocardial infarction, reduces blood pressure and prevents LDL cholesterol oxidation. High blood lycopene concentrations are also associated with lower risks of developing prostate, lung, uterine and breast cancer. Lycopene does not only inhibit proliferation of neoplastic cells, but it also induces their apoptosis and prevents metastasis.

The health effects attributed to this compound are mostly derived from its antioxidant properties. It is a strong singlet oxygen quencher, and it thwarts lipid oxidation. Experimental and clinical studies have also confirmed lycopene's positive effects on the skeletal system and on neurodegenerative diseases, including Alzheimer's and Parkinson's.

Introduction

Oxidative stress and low intake of fruits and vegetables in the diet are the greatest potential to promote disease and impair human health (Petyaev, 2016; Cheng et al., 2017). Current dietary guidelines to combat chronic diseases, including cancer and coronary artery diseases, recommend increased intake of plant foos, including fruits and vegetables, which are rich sources of antioxidants (Bacanli et al., 2017). Vegetables such as tomato are ubiquitous in most dietary patterns across the world, and their contribution to health has been documented in longitudinal epidemiologic studies (Slavin & Lloyd, 2012). Among the bioactive ingredients of tomato, lycopene is important to human health (Costa‐Rodrigues et al., 2018).

Decades of research into lycopene's significance in human nutrition and prevention of diseases of civilisation have shown it to be one of the strongest antioxidants among carotenoids, second only to astaxanthin (Hamułka & Wawrzyniak, 2004; Cho et al., 2018). Its antioxidative properties stem from the molecule's ability to deactivate (quench and scavenge) reactive oxygen species (ROS). Its effectiveness in removing singlet oxygen is double that of β‐carotene and ten times larger than that of α‐tocopherol (Krinsky & Johnson, 2005). In responding to oxidative stress, apart from neutralising ROS it also activates the expression‎ of genes encoding, inter alia, NAD(P)H:ubiquinone oxidoreductase (NQO1), haem oxygenase 1, glutathione reductase and glutathione S‐transferases (GSTs) (Breinholt et al., 2000). It modulates the activity of enzymes contributing to the formation of ROS, such as NADP(H) oxidase, cyclooxygenase‐2, 5‐lipoxygenase and induced nitric oxide (NO) synthase (Palozza et al., 2012). Lycopene's beneficial properties are emphasised in the context of cancers [mainly prostate cancer (PCa)] (Sahin et al., 2017). By preventing lipid, LDL fraction, protein and DNA oxidation, it protects the system from carcinogenesis and atherogenesis (Böhm et al., 2012). According to Salman et al. (2007), lycopene exerted a significant dose‐dependent effect on the proliferation capacity of K562, Raji and HuCC lines, whereas this effect was observed in EHEB cells only with the highest dose used in the study. Increased apoptotic rate was found after incubation of HuCC cells with 2.0 and 4.0 μm of lycopene and in Raji cells following incubation with 2.0 μm. Within the range of 20–60 μm, it inhibits the proliferation of cells and activates their apoptosis (Mohanty et al., 2005). It constrains cellular division in colorectal cancer, acute myelogenous leukaemia, AML, erythroid leukaemia and Burkitt lymphoma (Burgess et al., 2008). Cardiovascular diseases (CVD) are a significant group of conditions in the prevention and treatment of which lycopene plays an important role (Cheng et al., 2017). Its protective effect on the cardiovascular system stems from its antioxidative nature and ability to modulate cholesterol metabolism (Palloza et al., 2012). It prevents the oxidation of LDL cholesterol and reduces its overall level (Hu et al., 2008). Clinical studies carried out by Fuhrman et al. (1997) have shown that it reduces cholesterol synthesis (by up to 60–70%) in macrophage cultures by inhibiting HMG‐CoA reductase. In the study group patients, lycopene applied at 60 mg a day for 3 months caused a 14% reduction in plasma LDL cholesterol content. Moreover, lycopene helps lose body weight and contributes to improving the serum lipid profile at a level similar to that achieved by applying atorvastatin (a medication used to reduce cholesterol concentration). It significantly decreases the size of atheromatous plaques, which has been confirmed by the research performed by Kumar et al. (2017). Sołtysiak & Folwarczna (2015) study showed that lycopene can protect the bone system against osteoporosis. The latest epidemiological studies indicate that it also has neuroprotective properties in preventing and delaying Alzheimer's and Parkinson's diseases (Hwang et al., 2017; Cho et al., 2018).

It should also be noted that oxidative stress and the accumulation of ROS and NO may represent a major cause of lycopene depletion in ageing, cardiovascular disease and others (Petyaev, 2016). When double bonds are oxidised and broken by reactive oxygen and ROS, the lycopene molecule undergoes irreversible nonenzymatic degradation leading to the formation of various oxidative metabolites such as 2‐apo‐5,8‐lycopenal‐furanoxide, lycopene‐5,6,5′,6′‐diepoxide, lycopene‐5,8‐furanoxide and lycopene‐5,8‐epoxide isomers (Müller et al., 2011). On the other hand, lycopene level in blood and tissues can be significantly affected by enzymatic degradation leading to the formation of different end products. In particular, enzymatic cleavage of lycopene by lipoxygenase is accompanied by accumulation of 3‐keto‐apo‐13‐lycopenone and 15,15′‐apo‐lycopenal among other minor cleavage products (Ferreira et al., 2003). Therefore, the disease whose conditions accompanied by long‐lasting oxidative stress may cause lycopene depletion and require constant and efficient replenishment of carotenoids in the antioxidant of human cells and tissues.

The aim of this paper was to review the state‐of‐art knowledge about lycopene and its impact on the risk of chronic diseases including cancer.

Chemistry, stability and sources of lycopene in food

Lycopene (ψ,ψ‐carotene) belongs to carotenoids, a group of over 750 pigments synthesised by higher plants, fungi, bacteria and algae. Animals, including humans, are unable to synthesise them, which is why they need to consume them with food (Maiani et al., 2009; Moise et al., 2014). Of the abundant family of carotenoids, approx. 60 are found in food, but only twenty can be detected in human blood and tissues. In functional and structural terms, they are a diverse group of polyene pigments. Thanks to having conjugated bonds (at least 7), they give colour to food, which ranges from yellow to orange to red (Kaulmann & Bohn, 2014). The differences in the structure of the polyisoprenoid chain allow us to distinguish between two groups of carotenoids: carotenes (lycopene, α‐carotene and β‐carotene) and xanthophylls (zeaxanthin, lutein, astaxanthin and canthaxanthin) (Juola et al., 2008; Gryszczyńska et al., 2011). The first carotenoids were isolated in the 19th century, but only the development of chromatographic methods in the early 20th century allowed for intensive research into their properties and their thorough chemical analyses to begin. In 1875, French botanist Pierre‐Marie‐Alexis Millardet was the first to isolate a dark red pigment from tomatoes (Lycopersicon esculentum L.), which was identified as lycopene, after which Richard Willstätter determined its molecular formula (C40H56) (Britton, 1995; Wawrzyniak et al., 2015).

Contrary to most carotenoids, lycopene has a linear structure. It is assembled of eight isoprene units that make up a 40‐carbon‐atom chain containing eleven conjugated and two unconjugated double bonds (Petyaev, 2016). This distinctive conjugated polyene structure accounts for the ruby colour and the antioxidant properties of lycopene (Shi & Le Maguer, 2000). It has a distinct lipophilic character, which makes it nearly insoluble in ethanol, methanol and water. Due to its acyclic structure and the absence of a β‐ionone ring, there is no pro‐vitamin A activity to be found in lycopene, which is the reason for its differing biochemistry, as compared to α‐ and β‐carotene (Milani et al., 2017). In nature, lycopene occurs mainly as all‐trans‐isoform, often referred to as all‐E‐lycopene. All‐trans‐lycopene is thermodynamically the most stable form (Jackson et al., 2008). Lycopene's double bonds can undergo isomerisation from all‐trans to mono‐ or poly‐cis forms under the effects of light, temperature or chemical reactions. This is why approx. 90% of lycopene found in tomatoes is in the form of all‐trans‐isomers, while more cis‐isomers are found in processed products (Rao & Agarwal, 1999). Cis‐isomers of lycopene are believed to be more bioavailable for humans (Honda et al., 2018).

It is well known that food processing can have many effects, not all of which result in a loss of quality and health properties. This is the case for some carotenoids, such as lycopene or β‐carotene, which were found to be very heat stable even after intense or prolonged heat treatments such as sterilisation processes or cooking (Nicoli et al., 1999) (Przybylska & Felisiak, 2012). Since lycopene is responsible for the red colour of tomatoes and colour is used as an index of quality for tomato products, minimising the loss of lycopene throughout the production process and during storage is always important. Being acyclic, lycopene possesses symmetrical planarity, and as a highly conjugated polyene, it is particularly susceptible to oxidative degradation. Physical and chemical factors such as elevated temperature, exposure to light, oxygen, extremes in pH and molecules with active surfaces can destabilise the double bonds of lycopene (Scita, 1992). Cole & Kapur (1957a, 1957b) examined the kinetics of lycopene degradation by studying the effects of oxygen, temperature and light intensity on the formation of its volatile oxidation products. Adding to Monselise & Berk's (1954) report of oxidative degradation of lycopene in heat‐treated tomato puree, Cole & Kapur (1957b) reported significant losses of lycopene in serum‐free tomato pulp samples following thermal treatment at 100 °C in the presence of oxygen, with or without light. The intensities of illumination and temperature were found to be in direct correlation with lycopene degradation in the presence of oxygen. Undesirable degradation of lycopene affects not only the sensory quality of the final products but also the health benefit of tomato‐based foods for the human body (Huawei et al., 2014). Lycopene is more stable in native tomato fruit tissues and matrices than in isolated or purified form as a result of the protective effects of cellular constituents such as water. Therefore, care must be taken to minimise the loss of lycopene through oxidation or isomerisation during extraction, storage, handling and analysis to accurately account for cause–effect changes. In lycopene context, food processing is in fact a value‐added step, in that more lycopene becomes bioavailable following thermal treatment. Heating of tomato juice was shown to result in an improvement in uptake of lycopene in humans (Stahl & Sies, 1992). Agarwal et al. (2001) showed that lycopene content of tomatoes remained unchanged during the multistep processing operations for the production of juice or paste and remained stable for up to 12 months of storage at ambient temperature. Moreover, subjecting tomato juice to cooking temperatures in the presence of corn oil resulted in the formation of the cis‐isomeric form, which was considered to be more bioavailable.

Since humans are unable to synthesise lycopene de novo, sufficient uptake from the diet is necessary to benefit from its health‐promoting effects.

The main sources of lycopene in the diet are tomatoes and tomato‐based products (80%) (Maiani et al., 2009). The amount of lycopene present in processed tomato products is often much higher in fresh tomatoes given that processing often involves concentration via water loss (Bacanli et al., 2017). However, the lycopene content of fresh tomato is highly variable, being affected by factors such as variety, ripeness, climate and geographical site of cultivation (She & Le Maguer, 2000). Tomatoes grown in Poland have a ψ,ψ‐carotene content ranging from 1.21 mg 100 g−1 to 6.43 mg 100 g−1. However, its average content in intensely red cultivars grown in summer (5.6 mg 100 g−1) is twice as high as in lighter cultivars (2.6 mg/100) grown in spring or autumn (Wawrzyniak et al., 2005). In the author's own study (Przybylska et al., 2009), summertime ‘Ika' cultivar tomatoes demonstrated a high lycopene content (5.12 mg 100 g−1), as well. The most lycopene is found in tomato concentrates (54 mg 100 g−1) and dried tomatoes (46.5 mg 100 g−1). Other products have varying quantities, and thus, ketchups contain 16.6 mg 100 g−1, tomato juices 5–7 mg 100 g−1, and powder soups and sauces 20.86 mg 100 g−1 and 23.88 mg 100 g−1 of lycopene, respectively (Hamułka & Wawrzyniak, 2004; Colle et al., 2010).

Apart from tomatoes, lycopene is also found in papaya (2.0–5.3 mg 100 g−1), watermelon (2.3–7.2 mg 100 g−1), pink grapefruit (0.35–3.36 mg 100 g−1), dog rose (0.68–0.71 mg 100 g−1), carrot (0.65–0.78 mg 100 g−1) and pumpkin (0.38–0.46 mg 100 g−1) (Bohm et al., 2003; Markovic et al., 2006). Next to tomato peels, watermelon pulp can also be used for lycopene extraction (Oberoi & Sogi, 2017) and is a rich source of cis‐isomeric lycopene, abundant in higher concentrations than in tomatoes (Naz et al., 2014). Interestingly, also the fungal plant pathogen Blakeslea trispora has been recognised as a commercial source to produce lycopene (Mantzouridou & Tsimidou, 2008). Several foods high in lycopene content are classified as functional foods (Naz et al., 2014). Tomato juice, paste, puree, ketchup, sauce or soup represents lycopene sources with improved bioavailability due to thermal treatment, but also because processing releases lycopene from the fibrous cell structure matrix (Burton‐Freeman & Sesso, 2014).

Dietary intake levels and safety of lycopene

The US Food and Drug Administration in America granted Generally Recognized as Safe status to lycopene as a nutritional supplement (Rao et al., 2006). Dietary intake of lycopene varies due to populations. Lycopene intake in Italy with an average intake of 7.4 mg day−1 is greater than in other European countries outside Poland (7–7.5 mg day−1) (Hamułka & Wawrzyniak, 2012). The average intake of lycopene is 6.6–10.5 mg day−1 for men and 5.7–10.4 mg day−1 for women in the United States, 1.1 mg day−1 in the United Kingdom, 1.6 mg day−1 in Spain, 3.8 mg day−1 in Austria, 4.8 mg day−1 in France and 4.9 mg day−1 in the Netherlands (Story et al., 2010). Higher intake of lycopene at daily dosage up to 100 mg has no side effects in volunteers (Shao & Hathcock, 2006). No evidence of toxicity of lycopene has been obtained from in vivo studies using laboratory animals (Jonker et al., 2003). Clinical studies use moderate amounts of lycopene rarely exceeding 10 mg day−1. However, in animal experiments daily supplementation up to 200 mg kg−1 has been reported (Gupta et al., 2003). Therefore, low toxicity and high tolerance of lycopene open the door to various options in the design of lycopene supplementation protocols. According to Rao et al. (2007), the daily ψ,ψ‐carotene consumption level that ensures protective effects on the system is from 5 to 7 mg day−1. However, it has also been shown that disordered conditions such as overt cancer even require daily doses of up to 75 mg lycopene to reduce a further progression of the disease (Guo et al., 2015).

Metabolism of lycopene, its bioavailability and distribution in the body

Lycopene is a lipophilic tomato pigment which, provided through diet, is digested in the gastrointestinal tract in an amount ranging from 10% to 30% (Rao & Rao, 2007). Due to its hydrophobic properties, it can also be digested if assisted by lipids and bile acid salts, with which it forms micelles. In the stomach and duodenum, the consumed lycopene dissolves in the lipid phase which, under the influence of pancreatic lipases and bile acid salts, becomes dispersed (Kong et al., 2010). In the duodenum, multilayered liposomes are formed which, through passive transport, are absorbed through the wall of the intestine. Apart from passive transport, lycopene absorption can also occur with the help of carotenoid transporters found in the intestinal epithelium (Wang, 2012). After it is absorbed from the gastrointestinal tract, lycopene is – with the intermediation of chylomicrons formed in enterocytes – released into the subepithelial lymphatic vessels and transported to the liver. There, it creates complexes with low‐density (LDL) and very‐low‐density (VLDL) lipoproteins, which then return to blood circulation and transfer lycopene to such organs and tissues as adrenals, kidneys, spleen, lungs and reproductive organs, and to the adipose tissue. Lycopene is drawn by tissues from the VLDL and LDL complexes in the presence of LDL receptors, and its concentration in the individual organs is diversified by the varying activity if these receptors are on the surface of the cells (Boileau et al., 2002).

Lycopene is the most abundant carotenoid in human plasma. Its average level depends on the nutritional habits and ranges from 0.11 μm (in the Japanese population) to 1.32 μm (in the Italian and Greek populations) (Kong et al., 2010). According to some sources, lycopene's half‐life in the plasma/serum is 2–3 days (Rao & Rao, 2007) or 12–33 days according to others (Wang, 2012).

Dietary lycopene absorption is affected by a number of boosting or limiting factors. Especially, the inclusion of 5–10 g of fat in the meal has an optimal supporting effect on lycopene absorption. Absorption is also affected by the type of fatty acids and by warming that leads to lycopene being released from the protein bonds. On the other hand, the presence in food of, inter alia, fibre, plant sterols and statins binds ψ,ψ‐carotene, thus preventing its absorption. These agents are assumed to reduce its serum concentration by as much as 40% (Belter et al., 2011). The effects of processing and storage on lycopene structure and stability are of interest for a number of reasons. Improper processing and storage (i.e. exposure to light and oxygen) may alter the ratio of lycopene isomers or degrade lycopene entirely, making these food products less desirable to the consumer (Xianquan et al., 2005). Isomerisation of lycopene affects its absorption efficiency. Perhaps, all‐trans‐lycopene, a long linear molecule, may be less soluble in bile acid micelles. In contrast, cis‐isomers of lycopene may move more efficiently across plasma membranes and preferentially incorporate into chylomicrons (Erdman, 2005). Traditional commercial processing methods do not have a significant effect on lycopene levels or on cis/trans isomerisation. In fact, thermal processing generally improves lycopene bioavailability by disrupting cellular membranes, which allows lycopene to be released from the tissue matrix. Multiple studies have shown that lycopene from thermally processed tomato products is more bioavailable than lycopene from fresh tomatoes (Thies et al., 2012). However and according to Cheng et al. (2017), the absolute amount of lycopene absorbed seems to be more dependent on inter‐individual differences rather than on its dose. A human study shown that a combination of salad dressing and canola oil increased lycopene content in plasma chylomicrons as compared to fat‐free salad dressing (Brown et al., 2004). This is in agreement with the results of Fielding et al. (2005) showing that tomatoes cooked with olive oil greatly increase the lycopene level in human plasma as compared to the tomatoes cooked without olive oil.

Lycopene concentrations in individual tissues range from 0.2 to 21.6 nmol per gram of tissue and depend on the type of the tissue concerned, the person's diet, lycopene bioavailability, the effectiveness of lycopene excretion and the different levels of activity of the lipoproteins found on the surfaces of the cells (Golarczyk & Siler, 2004). The highest level of lycopene is identified in the testicles, adrenals, prostate and liver and the adipose tissue, with the lowest (0.3–0.7 nmol per gram of tissue) found in the pancreas and kidneys. Lycopene metabolism is contributed by carotenoid dioxygenases (CCD) and β‐carotene monooxygenases (Nikki & Erdman, 2012).

ψ,ψ‐Carotene and its derivatives demonstrate a strong tendency to accumulate in tissues. After 96 h of application, as much as 24% of the consumed lycopene remains in the system. Lycopene metabolites are mainly excreted with urine and bile, and penetrate into the milk of lactating mothers (Belter et al., 2011).

It is assumed that oxidative stress as well as hyperactivity of the endogenous enzymes responsible for generation of ROS and NO may deplete lycopene reserves in human cells and tissues (Graham et al., 2012). Plasma lycopene level can become significantly reduced during the process of ageing. Older individuals show statistically lower lycopene concentration values in blood as compared to younger matching individuals with similar ethnic and dietary background (Semba et al., 2010). Acute and chronic gastritis and abnormal gastric acid secretion as well as deviations in intestinal enzyme spectrum during ageing are considered to be major causes of reduced intestinal carotenoid absorption in older individuals (Akhtar et al., 2013).

Antioxidative properties of lycopene, its mechanism of action, effectiveness and interactions with other antioxidants

Oxidative stress is considered to be one of the main causes of the diseases of civilisation. However, antioxidants, including lycopene, are assumed to be able to limit or prevent the development of various conditions caused by ROS. Their presence resulting from the lack of pro‐oxidative–antioxidative balance (redox‐ox) leads to DNA, lipid and protein damage and, also, deregulation of the cell cycle (Liou & Storz, 2010). The reactivity of carotenoids, especially lycopene in biological system, depends on their molecular and physical structure, location or site of action within the cells, ability to interact with other antioxidants, concentration and the partial pressure of oxygen (Young & Lowe, 2001). Biologically, lycopene tends to act as singlet oxygen (1O2) and peroxyl radical scavenger (LOO•) (Stahl & Sies, 2003). Lycopene degradation may result in colour loss when exposed to free radicals or oxidising agents. This is due to the reaction with free radicals and causes interruption of the polyene chain, in which the conjugated double‐bond system may be affected by either cleavage or addition to one of the double bonds (Krinsky & Johnson, 2005). Lycopene's antioxidant properties are mostly related to its eleven conjugated double bonds, in which π electrons are delocalised along the entire length of the polyene chain, thus enabling chemical reactions with molecules containing unpaired electrons to occur. They are the result of the transfer of an electron from lycopene to the radical, addition of the radical to the polyene chain or removal of a hydrogen atom from lycopene (Belter et al., 2011). Lycopene is understood to neutralise ROS twice as effectively as β‐carotene and ten times as effectively as α‐tocopherol. It shows particularly strong effects on hydroxyl radical (OH∙), nitrogen dioxide (NO2∙) and thiyl radical (RS∙) (Böhm et al., 2012).

The mechanism of action for lycopene towards the reactive species can be predicted through three possible mechanisms: (i) adduct formation: Lycopene + R• → R‐Lycopene•, (ii) electron transfer to the radical: Lycopene + R• → Lycopene•+ + R− and (iii) allylic hydrogen abstraction: Lycopene + R• → Lycopene• + RH (Krinsky & Johnson, 2005).

Adduct formation is the formation of resonance‐stabilised carbon‐centred peroxyl radicals where the free radical will attach to the polyene chain, the highly conjugated double bonds of lycopene, to form a lycopene–peroxyl radical adduct (ROO‐lycopene•) (El‐Agamery et al., 2004). This reaction is described in (i) where the lipid peroxyl radical (ROO•) reacts with lycopene. Under high oxygen concentrations, the ROO‐lycopene• may possibly react with O2 to form a new radical. This reaction was reported as reversible and related to the pro‐oxidant effect which may occur in carotenoid compounds (Krinsky & Yeum, 2003). The pro‐oxidant effect of the peroxyl radical–lycopene adduct (ROO‐lycopene•) can be explained if this compound is further reacted with oxygen forming a new lycopene–peroxyl radical (ROO‐lycopene‐OO•). This intermediate species (ROO‐lycopene‐OO•) will subsequently act as a pro‐oxidant or initiator for lipid peroxidation by reacting with lipid (RH) and forming another peroxyl radical (ROO•) with oxygen (O2). However, the peroxyl radical–lycopene adduct may also be terminated in the occurence of another peroxyl radical by forming the inactive end products (Krinsky & Johnson, 2005).

Again, the modes of action for antioxidants were depended on their position in the cell. Carotenes such as lycopene lie parallelly with the membrane surface. Thus, lycopene is expected to be a poor antioxidant due to its limited interaction with aqueous phase radicals in the lipid bilayer as compared to more polar carotenoids such as zeaxanthin (Young & Lowe, 2001). Besides, high concentration of lycopene in the membranes may cause aggregation that may affect the properties of membrane by leading to increase in membrane fluidity and permeability, and finally will result in pro‐oxidant type effects (Stahl & Sies, 2005). However, lycopene is still important in inhibiting lipid radicals at membranes as the first defence system of cells. The combinations of lycopene and other antioxidants such as vitamin C, vitamin E and β‐carotene have exhibited higher scavenging activity on 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical than their individual antioxidant activity (Liu et al., 2007). Besides, lycopene combined with other antioxidants also gave a better inhibiting effect towards diene hydroperoxides produced from linoleic methyl ester with 2,2′‐azobis (2,4‐dimethylvaleronitrile) (AMVN)‐induced oxidation (Shi et al., 2007). Lycopene was also reported to help in repairing the vitamin E radical, and the products from this reaction radical cation will be repaired by vitamin C.

Lycopene, similarly to β‐carotene which is present in human skin, demonstrates an ability to absorb radiation and eliminates ROS induced by UV radiation. Of these two compounds, lycopene suffers more damage as a consequence of skin exposure to UV light, which points to lycopene's important role in mitigating photooxidative damage. Lycopene's sunscreen effects are understood to be associated with, inter alia, the reduction of UV‐induced erythema. A long‐term diet incorporating 40 g of tomato paste a day, which contains 16 mg of lycopene, increases its serum and skin content and significantly reduces the formation of UV‐induced erythema. Similar effects have been obtained by using synthetic lycopene, tomato extract and a beverage with solubilised forms of the supplement (Aust et al., 2005).

Apart from its antioxidative properties, lycopene and its derivatives (apo‐10′‐lycopenal, apo‐10′‐lycopenol and apo‐10′‐lycopenoic acid), in response to oxidative stress, induce the activity of antioxidative and detoxifying proteins, which constitutes an effective method for protecting the cell against both reactive metabolites and ROS (Linnewiel et al., 2009). Increased lycopene concentrations in the cell cause the Nrf2 complex present in the cytoplasm to disintegrate and the Nrf2 transcription factor to be translocated into the nucleus, where – by binding to the antioxidant response elements (ARE) autonomously replicating sequence – it induces the expression‎ of enzymes neutralising radicals and toxins (Wakabayashi et al., 2010).

Preventive effect of lycopene towards diseases

The first reports on lycopene's beneficial effects on humans were published over 50 years ago. At that time, the scientists observed a relationship between the amount of lycopene applied to animals and their resistance to infection or the development of abdominal cancer. Although lycopene was discovered a long time ago, its new health effects are still being discovered.

Effect of lycopene on the risk of cardiovascular disease

Cardiovascular diseases are the leading cause of premature deaths in most highly developed countries (Jankowski, 2017). Poor lifestyles, unbalanced nutrition and limited physical activity are the main causes of myocardial infarction, atherosclerosis and stroke (Balsam & Grabowski, 2014). High plasma low‐density lipoprotein (LDL) concentrations, as well as the oxidation state of the LDL fraction, correlate with the increasing preval‎ence of the aforementioned diseases. Although there are many therapeutic methods making use of thrombolysis or angioplasty available today, special attention needs to be paid to primary prevention and thus the diet (Tong et al., 2016). Therefore, the inclusion of sufficient fruits and vegetables in the diet is regarded as especially important. The preval‎ence of cardiovascular disorders is remarkably unevenly distributed in developed countries, and some areas, for example, Southern Europe, seem to be protected by having significantly less preval‎ence of the disease. This effect has often been attributed to dietary factors, as for example, the Mediterranean diet, with a lot of fruits and vegetables, including tomatoes, tomato products and olive oil (Krasinska et al., 2017). Tomatoes, tomato sauce and watermelon are important sources of lycopene and may be a surrogate for the Mediterranean diet to some degree (Naz et al., 2014). Therefore, a high supply of dietary lycopene could be used both for prevention and for therapy of CVDs (Petyaev, 2016). Lycopene, as a carotenoid showing the high antioxidant potential, is also capable of modulating a number of factors, such as inflammation, apoptosis or inter‐cellular communication, which are important in the context of these conditions (Thies et al., 2017). The main disadvantage of lycopene is related to its low bioavailability, which depends not only on the different lycopene biochemical isoforms, but also on the context of ingestion and on the genetics of each individual (Zubair et al., 2015). Many studies about the relationship between lycopene and cardiovascular risk have been conducted, and although some of the results are inconsistent, overall dietary lycopene intake and high serum concentration of lycopene significantly reduced the risk of major cardiovascular events (Cheng et al., 2017; Song et al., 2017). Not only lycopene intake counts, but also its serum concentration may influence cardiovascular risk. Low serum and adipose tissue lycopene levels were correlated with early atherosclerosis and major acute coronary and cerebrovascular events and were found to be more reliable in risk assessment than the daily intake of lycopene (Kim et al., 2011). Oxidative stress and inflammation are responsible for a reduced level of antioxidants (Kim et al., 2010). Smoking is a potent oxidative stressor, able to impair arterial elasticity and endothelial function (Mozos et al., 2018), and lycopene was the only major serum carotenoid able to reduce the atherosclerotic risk in current and former smokers according to the Rotterdam Study (Klipstein‐Grobusch et al., 2000). Oxidative stress causes endothelial dysfunction due to uncoupling of the NO synthase and oxidative injury of the endothelial cells (Mozos & Luca, 2017). Both are associated with inflammation. By reducing oxidative stress and ROS, lycopene increases the bioavailability of NO, improves endothelium‐dependent vasodilation and reduces protein, lipids, DNA and mitochondrial damage (Naz et al., 2014; Nakamura et al., 2017). Watermelon supplementation, due to l‐citrulline content, increases plasma l‐arginine, enabling NO production (Figueroa et al., 2017), because NO is synthesised from l‐arginine by NO synthase in virtually all cell types (Jobgen et al., 2006). Lycopene supplementation improved endothelial‐mediated vasodilation in cardiovascular disease patients, but not in healthy controls (Gajendragadkar et al., 2014), suggesting the importance of lycopene in secondary cardiovascular prevention (Costa‐Rodrigues et al., 2018). Hung et al. (2008), revealed that lycopene can inhibit TNF‐alpha‐induced NF‐kappa B activation, expression‎ of intracellular adhesion molecule‐1 and interaction between monocytes and endothelial cells, which might explain the cardiovascular benefits of lycopene. Lycopene can also reduce the secretion of metalloproteinases by macrophages and inhibit T lymphocyte activation (Thies et al., 2017). He et al. (2016) reported the benefits of lycopene in preventing transplant vasculopathy, demonstrating that intimal hyperplasia and smooth muscle cell proliferation were reduced by the administration of lycopene and the infiltration of inflammatory cells in allograft vessels was reduced in an animal model. According to the authors, lycopene can ameliorate allograft atherosclerosis via down‐regulating Rho‐associated kinases and regulating the expression‎ of key factors through NO/cGMP pathways. On the other hand, the benefits of the tomato‐rich diet were not directly related to the anti‐inflammatory effect according to a randomised study including 103 apparently healthy volunteers, after 300 g tomatoes daily for 1 month or placebo (Blum et al., 2007). Korean studies have shown that persons with high lycopene concentrations demonstrated a 5% drop in the arterial stiffening index which is used to indicate early atherosclerotic lesions. This mechanism of lycopene function is related to limiting the unfavourable oxidation of LDL (bad) cholesterol, which is likely to cause the formation of pathological lesions within the structure of blood vessels, such as the atheromatous plaque (Kim et al., 2010; Cheng et al., 2017). Lycopene is a regulator of cholesterol levels by inhibition of HMG‐CoA reductase (like statins) and down‐regulation of proprotein convertase subtilisin/kexin type 9 mRNA synthesis. These results suggest that lycopene supplementation could be especially beneficial for patients with statin intolerance (Alvi et al., 2017). In animal studies, Hu et al. (2008) eval‎uated the antiatherogenic effect of lycopene in rabbits fed a high‐fat diet. Lycopene was supplemented intragastrically at a dose of 4–12 mg kg−1 for 4 and 8 weeks. The carotenoid markedly reduced the formation of atherosclerotic plaques in the aorta from rabbits in their study. Such an effect was accompanied by a decrease in the levels of total cholesterol (TC), total triacylglycerol, LDL cholesterol, malondialdehyde, oxidised LDL and interleukin‐1, and by an increase in total antioxidant capacity and NO. Interestingly, these effects were more remarkable than those obtained by fluvastatin administration (10 mg kg−1). In the same animal model, supplementation with three doses of lycopene in the chow for 12 weeks dose‐dependently decreased diet‐induced serum TC and LDL cholesterol levels and increased HDL cholesterol (Verghese et al., 2008). In contrast, supplementation with a lycopene‐enriched tomato extract (15 mg kg−1 body weight per day lycopene) in the diet for 16 weeks had no effect on plasma cholesterol levels in Watanabe heritable hyperlipidaemic rabbits (Frederiksen et al., 2007). The reason for the lack of effects of lycopene in these rabbits may originate in defective LDL receptors. Since lycopene is transported in the blood mainly in LDL particles, a functional LDL receptor may be essential to obtain cardiovascular beneficial effects of lycopene. Mulkalwar et al. (2012), tested the hypolipidaemic and antioxidant effect of pure lycopene powder in hyperlipidaemic NZW rabbits. The carotenoid was administered at the dose of 10 mg kg−1 body weight per day for 6 weeks. There was a significant decrease in the level of serum TC and LDL cholesterol and an increase in serum HDL cholesterol following the addition of lycopene to a high‐fat diet. The therapeutic effect of lycopene‐rich tomato juice against evoked cardiac disorders in rats fed on fried potato in oxidised frying cottonseed oil (20% w/w) for 4 weeks was studied using lycopene at a daily dose of 1 mg kg−1 body weight (Hassan & Edrees, 2004). The obtained results revealed that feeding on fried potato in deep oxidised fryingoil induced a notable increase in lipid profiles and LDL cholesterol associated with a marked elevation in specific heart enzymes, LDL, CK, ALT and AST activities. These biochemical alterations ameliorated when lycopene was administered to rats fed fried potato in oxidised frying oil. Lycopene‐rich tomato juice induced a significant decrease in total lipids, TC, triglycerides and phospholipids as well as LDL cholesterol and a marked elevation in HDL cholesterol. These effects may be due to the ability of lycopene in protecting LDL from oxidation, to its role in inhibitingHMG‐CoA reductase activity and to up‐regulate LDL receptor activity in macrophages as well as to its powerful efficacy in neutralising free radicals (Heber & Lu, 2002). In agreement with the experimental observations on people, dietary supplementation of lycopene (60 mg day−1) to six men for a 3‐month period resulted in a significant 14% reduction in their plasma LDL cholesterol concentrations (Fuhrman et al., 1997). Supplementation with tomato extract capsules (4 mg lycopene) daily for 6 months decreased TC and LDL cholesterol levels in postmenopausal women (Misra et al., 2006). Moreover, a reduction in LDL cholesterol to 17% by tomato juice has been reported (Silaste et al., 2007). British studies have shown that daily ingestion of 27 mg of lycopene with tomato juice (400 mL) for 3 weeks decreases TC by 6% and LDL fraction by 13% (Silaste et al., 2007). Research carried out by Cuevas‐Ramos et al. (2013) showed that a daily diet of 300 g of raw tomatoes (Roma) for a month has been shown to increase the level of the HDL fraction in people. A significant increase in HDL‐C levels was observed in the tomato group (from 36.5 ± 7.5 mg dL−1 to 41.6 ± 6.9 mg dL−1, P < 0.0001 vs. the control group – eating cucumber in the diet). After stratification by gender, the difference in HDL‐C levels was only significant in women. The mean HDL‐C increase was 5.0 ± 2.8 mg dL−1 (range 1–12 mg dL−1). Twenty patients (40%) finished the study with levels >40 mg dL−1. Seven‐year‐long studies on men have proven that high lycopene levels are associated with, inter alia, inhibition of the atherosclerotic process in the carotid arteries by reducing intima‐media thickness. Also, an inverse relationship has been shown to exist between lycopene levels and the concentrations of one of the atherosclerotic process markers, namely C‐reactive protein. Its reduction has a direct effect on the pace at which the atheromatous plaque forms (Karppi et al., 2013a, 2013b). Consumption of 10 mg of lycopene a day reduces the risk of coronary heart disease by 50% (Sesso et al., 2004). According to Sawardekar et al. (2016), lycopene directly protects endothelial cells from oxidative damage, inhibits the interactions between monocytes and the endothelium and reduces plaque aggregation. Moreover, it suppresses neutrophil oxidative response and the secretion of pro‐inflammatory cytokines (Marcotorchino et al., 2012; Zou et al., 2013). An intake of over 12 mg of lycopene a day allows for decreasing systolic blood pressure by an average of 4.95 mmHg (Li & Xu, 2013). Experimental studies on a group of women in third trimester of pregnancy diagnosed with arterial hypertension have allowed for an observation that those of such patients who drink 250 mL of tomato juice a day have their systolic pressure to drop by 8.26 mmHg and diastolic pressure by 2.81 mmHg (Anita et al., 2017). Lycopene has antihypertensive effects due to inhibition of the angiotensin‐converting enzyme and due to its antioxidant effect, reducing oxidative stress induced by angiotensin‐II and indirectly enhancing production of NO in the endothelium (Belovic et al., 2016). A study including 8556 adult overweight and obese participants demonstrated association of lycopene and lycopene/uric acid ratio with lower preval‎ence of hypertension (Han & Liu, 2017).

Despite some controversy about specific effects of lycopene in cardiovascular protection, growing evidence points to unequivocal benefits of lycopene intake both in terms of cardiac, endothelial and vascular function and health.

Effect of lycopene on cancer risk

In recent years, a tomato carotenoid lycopene has gained attention for its potential health benefits, especially in prevention and treatment of cancer. The studies suggest that the consumption of lycopene in food or by itself may reduce cancer risk. However, there are insufficient clinical trial data to support the hypothesis. Lycopene may play a preventive role in a variety of cancers, especially in PCa. It acts by multiple mechanisms including the regulation of growth factor signalling, cell cycle arrest and/or apoptosis induction, metastasis and angiogenesis, as well as by modulating the anti‐inflammatory and phase II detoxification enzymes activities (Sahin et al., 2016). The effects can be attributed to the unique chemical structure of the carotenoid which confers it a strong antioxidant property.

Prostate cancer is the second most frequently diagnosed cancer worldwide, Its highest preval‎ence is observed in North America, Australia and West Europe, and the lowest in South‐East Asia (Holzapfel et al., 2013). One of the probable causes of PCa is the occurrence of mutations in the genes controlling cellular differentiation and growth. A chronic bacterial inflammation of the prostate gland may lead to the production of ROS that damage the DNA, thus causing mutations and, consequently, the development of tumour (Wertz, 2009). It is well understood that primary PCa growth is strongly dependent upon the activity of androgens within the prostate gland, as evidenced by the observed rise of androgen‐regulated prostate‐specific antigen (PSA) in the serum of men diagnosed with PCa (Pezaro et al., 2014). First‐line therapy for advanced or metastatic PCa involves the removal of tumour‐promoting androgens by androgen deprivation therapy (ADT), resulting in transient tumour regression. Recurrent disease is attributed to tumour adaptation to survive, despite lower circulating androgen concentrations, making the blockage of downstream androgen signalling a chemotherapeutic goal for PCa (Applegate et al., 2019).

Abundant epidemiological evidence indicates that tomato consumption and blood levels of the predominant carotenoid found in tomatoes, lycopene, are inversely associated with PCa risk (Xu et al., 2016; Rowles et al., 2018). Additional evidence suggests that tomato and lycopene interact with the androgen axis to reduce blood levels of PSA (Paur et al. 2017), as well as reduce the risk of advanced‐stage, lethal PCa (Wang et al., 2016). Animal and cell culture studies reveal an interaction between lycopene and androgen status and signalling, further indicating a potential protective role of tomato and lycopene intake for PCa patients. In LNCaP androgen‐dependent PCa cells, a lycopene concentration of 0.2 μm increases the number of detoxifying proteins, including epoxide hydrolase 1, which participates in the hydrolysis of epoxides to the less reactive dihydrodiols. What is more, it elevates the contents of superoxide dismutase (SOD1) responsible for ROS inactivation, catalase (CAT) responsible for decomposing hydrogen peroxide to water and oxygen, and transferrin (TF) responsible for binding iron and preventing the development of oxidative stress (Goo et al., 2007). The research carried out by Qiu et al. (2013) has shown for prostate epithelial cell (PrE) cultures that the activity of lycopene at a concentration of 2 μm for 48 h increases the expression‎ of phase II enzymes such as GSTs, peroxiredoxin 1 (PRDX1) and NAD(P)H reductase, and reduces the levels of proteins participating in the synthesis of such ROS as ERO1, CLIC‐1 and protein‐α. Through these effects, lycopene protects the cell from oxidative stress both by neutralising ROS and by activating protection mechanisms (Holzapfel et al., 2013). Moreover, the research carried out by Kotake‐Nara et al. (2001) has confirmed that out of fifteen different carotenoids, lycopene at a concentration of 5 μm demonstrates the largest inhibitory effect on PC3, DU145 and LNCaP PCa cell lines. In 2007, Ivanov et al.2007 compared two lycopene preparations: Lycopen™ and LycoTrue™ in order to study their effects on PC3 and LNCaP PCa cell lines. Their results pointed to the significant decrease in the LNCaP cell line proliferation rate under treatment with Lycopen™ at a concentration of 1 μm. At the same time, LycoTrue™ had a decreasing effect on the number of PCa cells at a concentration of 0.5 μm after 48 h of application. However, cell proliferation did not change after 24‐h activity or at a concentration of 0.25 μm. When repeated for PC3 PCa cell lines subjected to both these preparations, the experiment brought similar results to the ones presented above. Another 2011 study, in which DU145 PCa cell lines were used, found that lycopene caused proliferation rates to drop at concentrations of 15 and 25 μm, but not at physiological concentrations below 2 μm. Moreover, the decrease in the DU145 PCa cell line proliferation rate was mainly attributed to only one lycopene metabolite, namely apo‐12‐lycopenal, while any effects of apo‐8‐lycopenal were ruled out (Ford et al., 2011).

The antiproliferative and proapoptotic action of lycopene is related to its inhibitory effect on the expression‎ of genes encoding cell cycle proteins (Pallozza et al., 2012). Lycopene at a concentration of 5 μm induces stoppage of the cell cycle in the LNCaP PCa cell line both at the level of G0/G1 phase and G2/M phase transition. The first effects of cell cycle inhibition are observed after 24 h of applying lycopene at a concentration of 0.5 μm (Hwang & Bowen, 2005). Simultaneously, a drop in the level of cyclin D is observed, with an equivalent overexpression‎ of p21, p27, p53, Bax and Bcl‐2 proteins (Palloza et al., 2012). In DU145 PCa cell line cultures, lycopene at concentrations ranging from 15 to 25 μm inhibits cell proliferation, and in LNCaP cell line cultures, it causes the activation of the PPARγ‐LXRα‐ABCA1 pathway, which is responsible for inhibiting the growth of PCa cells (Yang et al., 2012a, 2012b). As reported by Lim et al. (2002), apoptosis induction by lycopene depends on the cell line studied, the concentration of lycopene and the duration of its application. In the relatively slowly growing cells of the LNCaP and DU145 lines, already at concentrations ranging from 1 to 3 μm lycopene will exert a proapoptotic effect, while in the considerably invasive cells of the PC‐3 line, lycopene is observed to have any effect only at concentrations starting between 20 and 60 μm (Holzapfel et al., 2013).

Moreover, lycopene can affect the invasion and migration of PCa cells by reducing the expression‎ of integrins–proteins that are overexpressed in aggressive PCa forms (Hall et al., 2006). Already at the low lycopene concentration of 0.01 μm applied to PC‐3 PCa cells, a decrease in the levels of such aggressive integrins as α2β1, αvβ3 and αvβ5 has been observed (Bureyko et al., 2009).

In animal studies, Imaida et al. (2001) have been the first to test the chemopreventive efficacy of lycopene using a chemically induced rat PCa model (6‐week‐old male F344 rats). After carcinogen exposure with 3,2′‐dimethyl‐4‐aminobiphenol for 20 weeks, lycopene purified from tomato extracts (99.9%, LycoRedTM, Beer Sheva, Israel) was incorporated in the basal diet (Oriental MF; Oriental Yeast co. Ltd, Tokyo, Japan) at a dosage of 15–45 ppm for 40 weeks. The authors found a significantly decreased incidence of prostatic intraepithelial. However, these results have not been reproducible in subsequent experiments (Imaida et al., 2001). Boileau et al. (2003) showed that supplementation with water‐dispersible beadlets of synthetic lycopene (Hoffman‐La Roche, Basel, Switzerland) at a concentration of 2.5 g of beadlets kg−1 of AIN‐93G diet had no effects on the PCa‐specific survival of male Wistar rats. To induce carcinogenesis, they were previously treated with cyproterone, testosterone and N‐methyl‐N‐nitrosourea. However, the authors found that powder derived from heat‐processed tomato paste (Armour/Del Monte Foods, San Francisco, CA, USA) incorporated into the diet at the same concentration as the synthetic lycopene was able to increase survival. Siler et al. (2005) used the MatLyLu cell line to establish prostate tumours in 8–10‐week‐old male Copenhagen rats. Supplementation of synthetic lycopene at a dosage of 200 ppm (lycopene 5% TG, DSM Nutritional Products, Basel, Switzerland) incorporated into a standard basal diet (Kliba #2019, Provimi Kliba AG, Kaiseraugst, Switzerland) for 4 weeks led to a significant increase in necrotic area within the tumours when compared to animals without lycopene supplementation. Hence, the authors suggested that lycopene can lead to a reduction of the prostatic tumour mass. The same group found that synthetic lycopene induces antiandrogen and anti‐inflammatory effects, both in cancerous and in healthy prostate tissue.

In 2005, Tang et al. (2005) analysed the effect of natural lycopene on the growth of androgen‐independent human DU145 PCa cells after subcutaneous injection (1 × 107 cells 100 μL−1 Matrigel™) into the flanks of 4–6‐week‐old male BALB/c nude mice. The lycopene formulation used consisted of >95% pure lycopene with 6% lycopene oleoresin extracted from tomatoes. After tumour cell injection, the mice were gavaged 5 days week−1 with different dosages of lycopene (0, 10, 100 and 300 mg per kg body weight) for 8 weeks. The authors showed a decrease in tumour growth by 55.6% and 75.8% in mice treated with 100 mg and 300 mg lycopene. Mice injected with DU145 cells pretreated with 20 μmol L−1 lycopene did not show any tumour formation after 1 month.

In 2010, Konijeti et al.2010 used a TRAMP model to compare the effects of lycopene beadlets (lycopene 10%, DSM Nutritional Products, Parsippany, NJ, USA) and tomato paste (Campbell's Soup Company, Camden, NJ, USA) on the incidence of PCa. Both supplements were incorporated into the basal AIN 93 diet with 100 mg lycopene per kg diet since the age of weaning. In contrast to previously published studies (Boileau et al., 2003), the authors found a significantly decreased incidence of PCa in those animals treated with synthetic lycopene, but not in the animals treated with the tomato paste. In 2011, Tang et al. (2011) investigated the effect of synthetic lycopene and docetaxel on the survival and growth rate of xenografted tumours. DU145 PCa cells were injected at a concentration of 1 × 106 cells 100 μL−1 PBS into the right flank of NCR‐nu/nu nude mice. After the tumours reached a size of approximately 200 mm3, the mice were treated either with 15 mg kg−1 body weight of synthetic microencapsulated lycopene (LycoVit™ 10% CWD, BASF Corporation, Shreveport, LA, USA) via gavage or with an intraperitoneal injection of docetaxel or with a combination of both. Docetaxel plus lycopene led to a significantly higher tumour regression and increase in survival when compared to docetaxel alone. The synthetic lycopene was able to enhance the antitumour capacity of docetaxel, even when it was given at a suboptimal dosing. However, lycopene alone had no effects on tumour regression or survival.

Yang et al. (2011) implanted human PC3 PCa cells (1 × 107 cells 100 μL−1 PBS) into the flanks of 6–8‐week‐old athymic nude mice. Subsequently, the mice were gavaged with 4 or 16 mg kg−1 body weight of lycopene (97%, Wako Pure Chemical Industries, Japan; purified from tomatoes) or 16 mg/kg β‐carotene suspended in corn oil twice a day for 7 weeks. The authors showed that both lycopene and β‐carotene were able to significantly decrease tumour volume and weight when compared to a control group without supplementation. At high dose level, lycopene and β‐carotene significantly reduced the expression‎ of proliferating cellular nuclear antigen in tumour tissues and increased insulin‐like growth factor‐binding protein‐3 levels in the plasma. In addition, lycopene supplementation at high dose level significantly reduced vascular endothelial growth factor in the plasma.

In addition to the above studies on animals, there are also those in which the effect of lycopene on androgen levels was assessed. In 2007, Canene‐Adams et al. 2007 analysed the effect of a 10% tomato powder (TP) diet and two different supplemental doses of lycopene (similar dose to the lycopene content of the TP diet and a dose 10‐fold higher) on serum testosterone and DHT levels in the Dunning R3327‐H transplantable prostate adenocarcinoma model after 18 weeks of tumour growth. None of the interventions had any effect on serum testosterone or DHT levels. Using the same model, Lindshield et al. (2010) similarly saw no effect of lycopene supplementation on serum testosterone or DHT levels. Siler et al. (2004) observed reductions in the expression‎ of genes involved in androgen metabolism (SRD5A1) and signalling (cystatin‐related proteins 1 and 2; prostatic spermine‐binding protein; prostatic steroid‐binding protein C1, C2 and C3; and probasin) in MayLyLu Dunning transplantable tumours with dietary lycopene intake. Only fold changes in gene expression‎ with no statistical measurements were reported; however, consistent with these results, Wan et al. (2014) confirmed that tomato feeding and lycopene supplementation similarly impacted androgen‐related gene expression‎ in the prostate of the transgenic mouse model (TRAMP) at early stages of prostate carcinogenesis. Tomato and lycopene diets both decreased the expression‎ of genes related to androgen metabolism (SRD5A2 by tomato and SRD5A1 by lycopene), while the tomato diet reduced the expression‎ of androgen co‐regulators paxillin (pxn) and sterol regulatory element binding transcription factor 1 (srebf1). It is important to note that no studies reported an increase in androgen levels or androgen‐regulated gene expression‎ with tomato or lycopene exposure, suggesting that neither tomato nor lycopene propagate androgen production or signalling (Applegate et al., 2019).

In general, cell culture studies supported the wide breadth of existing in vivo evidence that tomato and lycopene inhibit PCa tumour growth. Cell culture studies also provide some support for the limited in vivo evidence that tomato and lycopene down‐regulate the expression‎ of genes related to androgen signalling and metabolism. The included studies provided mixed evidence to indicate that lycopene interacts with AS (androgen‐sensitive) and AI (androgen‐insensitive) PCa cell lines in a differential manner and that lycopene directly interacts with the androgen axis. Liu et al. (2006) reported that lycopene uptake was much higher in AS LNCaP cells when compared to AI PC‐3 or DU145 cells. To eval‎uate whether this higher uptake resulted in direct lycopene binding to the AR, LNCaP cells were transfected with a plasmid containing the ligand‐binding domain of L701H, the T877A double mutant and cortisone/cortisol‐responsive AR with a broader ligand specificity (ARccr). No direct lycopene binding to the AR occurred, but subcellular fractionation revealed the majority of lycopene to localise within the nuclear membranes and nuclear matrix. Therefore, these data suggest that because lycopene uptake followed the order of AR expression‎ in AS and AI cell lines, lycopene uptake and storage may be mediated by androgen signalling by some mechanism not involving direct binding to the AR. Linnewiel‐Hermoni et al. (2015) showed that DHT‐induced growth of LNCaP cells and serum‐induced growth of DU145 and PC‐3 cells were inhibited by lycopene treatment. To determine whether these effects may be mediated by direct androgen responsiveness, LNCaP cells were transfected with a PSA enhancer luciferase reporter gene construct containing six AREs. Physiological levels of lycopene were not tested, but a high lycopene concentration (8 μm) was found to significantly lower the reporter activity after DHT treatment. Similarly, DHT‐induced PSA secretion by LNCaP cells was reported to be ~40% reduced by a more physiological, albeit still high, dose of lycopene (2.5 μm), but statistical analysis did not indicate a significant reduction. Liu et al. (2008) co‐cultured primary human prostate cancer stromal (6S) cells with primary normal prostatic epithelial (NPE) cells to determine the effects of DHT on camptothecin (CM)‐induced cell death by DNA fragmentation. DHT treatment increased the mRNA expression‎ of IGF‐I in 6S cells, which then led to the rescue of CM‐induced NPE cell death. Treatment of this co‐culture with physiological doses of lycopene (0.3 and 1 μm) inhibited the pro‐survival effects of DHT in a dose‐responsive manner, potentially due to the administration of lycopene decreasing DHT‐induced IGF‐I gene expression‎ in 6S cells. Furthermore, lycopene treatment inhibited DHT‐induced AR expression‎ in both whole cell lysates and nuclear extracts of 6S cells.

Rafi et al. (2013) showed that while strictly androgen‐regulated genes were largely unaffected in PC‐3 cells treated with supraphysiological doses of lycopene (25 μm), some genes within the kallikrein‐related peptidase family did show a fold reduction in expression‎ (klk1, 5, 9, 10, 14). These genes are regulated by members of the steroid hormone family and their expression‎ is typically associated with carcinogenesis, so a slight reduction in gene expression‎ by lycopene treatment may indicate some interference with steroid hormone‐regulated gene activation. It is important to note that similar to the effect estimates seen in the animal studies, no cell culture studies reported an increase in androgen‐regulated gene activity or expression‎ with lycopene exposure, despite a wide range of effect sizes, suggesting that lycopene has either a neutral or a inhibitory effect on androgen signalling (Applegate et al., 2019).

While the current pool of research is promising, there is a general lack of preclinical and clinical research relating to the effects or mechanisms of lycopene or other compounds present in tomatoes on androgens, their metabolites and their downstream effectors at different stages of PCa. Androgen signalling is an important chemotherapeutic target for advanced PCa because intratumoral signalling persists, despite the removal of androgens through ADT. Regular and feasible dietary intake of tomatoes has been shown to reduce the risk for PCa. The mechanisms behind this risk reduction are unclear; however, a reduction of androgen signalling would suggest an important role for tomato and tomato carotenoids at all stages of PCa growth and progression.

In vitro and in vivo studies suggest that intake of lycopene‐containing foods may reduce breast cancer risk. Assar et al. (2016) have recently reported that lycopene inhibits prostate as well as breast cancer cell growth at physiologically relevant concentrations ≥1.25 μm. Apart from PCa, breast cancer is the most preval‎ent cancer in Polish women and the second most preval‎ent one in world population. In breast cancer patients, lower levels of serum lycopene and its smaller dietary supply were observed when compared to healthy women (Simon et al., 2000; Levi et al., 2001). Studies on premenopausal women show that the risk of developing breast cancer is associated with high IGF‐1 levels (Krajcik et al., 2002). It has been found that the consumed lycopene reduces the blood concentration of IGF‐1 by stimulating the synthesis of an IGF‐1 binding protein (Karas et al., 2000). Moreover, lycopene applied during breast cancer radiotherapy demonstrates protective effects and reduces the side effects of radiation within the exposed skin (Di Franco et al., 2012).

A high exogenous or endogenous oestrogen concentration is one of the factors contributing to cancer cell hyperplasia and accelerated carcinogenesis in the aetiology of breast cancer (Peng et al., 2017). The possibility of carotenoids weakening the oestrogen‐induced mitotic activity has been shown in a study which has found that the dietary supply of α‐carotene, β‐carotene and lycopene reduces proliferation of cancer cells, although only those cells have active oestrogen and progesterone receptors (ER+/PR+) (Cui et al., 2008). In another paper, lycopene's ability to inhibit signalling in oestrogen‐dependent breast cancer cells was studied in vivo (Hirsch et al., 2007). The authors showed that lycopene extended the duration of G1/S phase transition in these cells. At the same time, both lycopene and other carotenoids competed with oestrogen for the active site in the nuclear oestrogen receptors ERα and ERβ. This phenomenon has been observed to decrease the transactivation of ERE (oestrogen response element) found in the DNA (Hirsch et al., 2007). In vitro studies on breast cancer cells have shown that lycopene inhibits the proliferation of both oestrogen‐dependent and oestrogen‐independent cells. This suggests that apart from affecting oestrogen receptors, lycopene simultaneously uses other mechanisms impacting the inhibition of proliferation, by for example inhibiting the activation of genes responsible for the cell cycle, or protein‐1‐responsive genes (Prakash et al., 2001).

For the MCF‐7 and MDA‐MB‐468 breast cancer cell lines, lycopene has been shown to demethylate the promoters of genes encoding the GSTP1, RARβ2 and HIN‐1 proteins that were first hypermethylated (King‐Batoon et al., 2008). In the course of oncogenesis, the RARβ2 receptor gene is silenced. Also, retinoic acid receptors (RAR) react with carotenoids such as α‐carotene, β‐carotene and lycopene (Bour et al., 2007). It has been shown for MCF10A cells sampled from patients with breast cysts that after the application of 2 μm of lycopene, the RARβ2 and HIN‐1 receptor genes become partly demethylated (Windschwendter et al., 2000). Other studies have suggested that lycopene inhibits MCF‐7 breast cancer cell hyperplasia by modulating the expression‎ of cytocreatine 19 and 8/18 (Uppala et al., 2013). In 2017, Peng et al. examined the effect of lycopene on proliferation of tumour cell and modulation of cancer progression as well as its possible underlying mechanisms in human breast carcinoma cell line MCF‐7 in vitro. MCF‐7 cells were treated with different lycopene concentrations (0, 2, 4, 8 and 16 μm) for different durations of 24, 48 and 72 h. Light field microscopy was used to observe cell morphology. MTT assay was used to determine the effect of lycopene on MCF‐7 proliferation. Flow cytometry was employed to eval‎uate cell apoptosis. Real‐time quantitative polymerase chain reaction was performed to detect the expression‎ of p53 and Bax. Under microscopic examination, the untreated MCF‐7 cells appeared to have a diamond or polygonal shape. These phenomena were aggravated with increasing concentrations and treatment durations. Lycopene significantly inhibited MCF‐7 cell proliferation in a dose‐ and time‐dependent manner. Significant inhibitory effects were observed with increasing concentrations or longer treatment periods. In particular, the most potent inhibitory effects on cell proliferation were observed in cells treated with 16 mm lycopene for 72 h. After treatment of MCF‐7 cells with different lycopene concentrations, apoptosis was detected using flow cytometry. Significant difference in cell apoptosis rate was observed between the control and lycopene‐treated groups. Cell apoptosis gradually increased with increasing lycopene concentrations, suggesting a dose‐dependent relationship. In addition, longer treatment durations increased the cell apoptotic rate. In addition, lycopene could also up‐regulate the expression‎ of p53 and Bax mRNAs in MCF‐7 cells. Results of the authors' research G0/G1 phase to inhibit MCF‐7 cell proliferation (Takeshima et al., 2014) and induce apoptosis (Teodoro et al., 2012) provided further evidences on the antitumour effects of lycopene on ER (+) breast cancer. The authors showed that lycopene induced apoptosis and inhibited MCF‐7 cell proliferation, possibly by regulating the expression‎ of p53 and Bax. However, owing to the inherent complicated mechanisms of breast cancer, future investigations using breast cancer in vivo model or other breast cancer cell lines are required to confirm‎ these findings.

Effect of lycopene on the risk of neurodegenerative disease

Neurodegenerative diseases are considered to be a serious medical problem in developed societies. Among them, Alzheimer's and Parkinson's diseases account for approx. 60% of cases. The increasing preval‎ence of these conditions is a result of not only population ageing, but first of all poor lifestyles. Unfavourable environmental processes, the intensifying ROS activity, inflammatory processes and, to a lesser extent, injuries and genetic predispositions are cited as the responsible factors (Cho et al., 2018). Alzheimer's disease is characterised by progressive reduction of cognitive functions, memory loss and behavioural disorders, all of which limit the patient's proper ability to function within the society (Mayeux & Stern, 2012). The classic symptoms of Parkinson's disease include slowness of voluntary movement (bradykinesia), difficulty in initiating movement (akinesia), tremor at rest and postural instability (Gorzkowska et al., 2011). These motor disorders are caused by damage to dopaminergic (dopamine‐synthesising) neurons located in the substantia nigra pars compacta which send their endings into the stratum (a subcortical structure). The characteristic set of clinical signs appears the moment the substantia nigra is degenerated in (and thus dopamine concentration is reduced by) approx. 60% (Chinta & Andersen, 2008).

Both these conditions belong to a group of progressive nervous system disorders characterised by the loss of neurons (Le Galès‐Camus, 2006). Neuronal death prevents synaptic signal transmission and disturbs the functioning of the nervous system (Mattson, 2004). The selective neuronal degeneration is accompanied by the emergence of pathological lesions arising from the aggregation of misfolded proteins. Protein deposits can form as a result of the aggregation of full‐length proteins (e.g. α‐synuclein in the neurons of Parkinson's patients) (Spillantini et al., 1997) or protein fragments by way of a specific proteolysis (e.g. the Aβ peptide deposited in the neurons of Alzheimer's patients (Agostinho et al., 2010)). The imbalance between Aβ production and removal becomes the reason for amyloid accumulation and amyloid plaque formation in the brain, thus changing the tissue's structure and function (De‐Paula et al., 2012). Neurofibrillary degeneration caused by spirally twisted fibres containing aggregates of excessively hyperphosphorylated tau protein is another important characteristic of the pathology of Alzheimer's disease (Cichacz‐Kwiatkowska et al., 2016). The hyperphosphorylated tau protein loses its capability to interact with tubulin, thus destabilising the structure of the microtubules. Moreover, it impairs axonal transport and synaptic function, this way causing neuronal death (Wolfe, 2012). In Parkinson's disease, dopaminergic neuron damage is accompanied by intracellular protein deposits of Lewy inclusion bodies, mainly composed of fibres of misfolded α‐synuclein and ubiquitin and parkin molecules (Lang & Lozano, 1998; Schlossmacher et al., 2002). A key role in the development of Parkinson's disease is played by α‐synuclein, which in healthy cells regulates the balance between vesicular dopamine and cytoplasmic dopamine. In a normal neuron, approx. 75% of dopamine should be found in the synaptic vesicles (Chinta & Andersen, 2008).

The neural tissue is particularly exposed to oxidative stress damage. This is an indirect result of the enormous oxygen demand of the nervous system. The brain, which accounts for a mere 2% of an adult's body weight, consumes approx. 20% of the total oxygen absorbed by the system. Moreover, the intensive oxygen metabolism results in an increased production of ROS, which form as side products of cellular respiration (Chong et al., 2005). The neuron cell membranes are particularly rich in polyunsaturated fatty acids, which makes them especially susceptible to oxidation. Additionally, the neural tissue in the central nervous system exhibits poor regenerative capabilities, which hinders its reconstruction and normal function following ROS‐induced damage (Barnham et al., 2004). Therefore, lycopene – because of its antioxidant properties – is of crucial importance here, as due to its lipophilic nature, it finds it easy to penetrate the blood–brain barrier and prevent lesions caused by oxidative stress (Wu et al., 2015). Research carried out by Hwang et al. (2017) has shown that lycopene inhibits neuronal apoptosis by reducing ROS, destroying β‐amyloid deposits and inhibiting mitochondrial dysfunction and NF‐kB‐target gene Nucling expression‎. To investigate the effect of lycopene, the cells (1 × 105/mL), either wild‐type or transfected, were pretreated with lycopene (0.2 or 0.5 μm) for 1 h and then stimulated with amyloid‐β (20 μm) for another 24 or 48 h. In the present study, lycopene significantly inhibited amyloid‐β‐induced increase in intracellular and mitochondrial ROS levels and apoptotic cell death in human neuronal SH‐SY5Y cells. Study showed that amyloid‐β (at concentration of 20 μm) induced maximal decrease in cell viability at the 24‐h culture rather than 48‐h culture. To determine whether amyloid‐β‐induced cell death is apoptotic, several apoptosis‐regulated genes, such as Bcl‐2 family genes and caspase‐3, were determined. In the present study, stimulation of amyloid‐β increased apoptotic indices including increase in the Bax/Bcl‐2 ratio, caspase‐3 activation and p53 expression‎. Treatment with lycopene reduced all these apoptotic responses in amyloid‐β‐stimulated cells. These results indicate that amyloid‐β caused neuronal apoptosis, which was inhibited by lycopene. The obtained results of the authors' research confirm‎ antiapoptotic effect of lycopene and its underlying molecular mechanism in amyloid‐β‐stimulated human neuronal SH‐SY5Y cells. Lycopene inhibits apoptosis by reducing intracellular and mitochondrial ROS, and by inhibiting mitochondrial damage and NF‐κB‐related Nucling gene expression‎ in amyloid‐β‐stimulated SH‐SY5Y cells. There is no treatment that can reverse the progression of Alzheimer's disease. Therefore, lycopene has the potential to be developed as a nutrient supplement for the prevention of AD clinically.

The main role in the development of neurodegenerative diseases is attributed to the interactions between mitochondria and mutated protein aggregates (Mattson et al., 2008). Misfolded proteins, such as β‐amyloid and tau protein which play a crucial role in Alzheimer's disease, and α‐synuclein in Parkinson's disease, affect the function of cell organs, including mitochondria. By disturbing their activity, these molecules disorder the homeostasis of the entire cell, which leads to the induction of apoptotic processes (Gręda & Jantas, 2012). Research into this type of lycopene's effect shows that apart from ensuring ROS reduction, it has a mitigating effect on neurotoxicity caused by the presence of β‐amyloid, tau protein and α‐synuclein deposits (Rahman & Rhin, 2017). Moreover, in their model research, Zhang et al. (2016) and Zhao et al. (2017) have shown that a lycopene‐rich diet reduces inflammation in neurons by inhibiting the activity of the NF‐kβ transcription factor and mitigates depression or cognitive function defects in the patient. Murine model studies have proven the protective properties of lycopene, which are associated with decreasing the number of dopaminergic neuron damages and curbing the drop in dopamine levels (Suganuma et al., 2002; Di Matteo et al., 2009). Recently, 8 weeks of lycopene treatment (5 mg kg−1) has been shown to reverse malondialdehyde (MDA) increase and glutathione peroxidase (GSH‐Px) decrease in serum in tau transgenic mice expressing P301 L mutation (Yu et al., 2017). These effects of lycopene in vivo appear to be beneficial for amelioration of neuronal damage because long‐term lycopene treatment (5 mg kg−1, 21 days) can reduce intracerebroventricular Aβ1‐42 injection‐induced caspase‐3 activation in the hippocampus in rats (Prakash & Kumar, 2014). In vitro studies have reported that lycopene pretreatment at doses ranging from 0.1, 0.5, 1, 2, to 5 μm reduces Aβ exposure‐induced cellular damage in a dose‐dependent manner via amelioration of mitochondria‐associated pathogenesis in primary cultured rat cortical neurons, such as mitochondrial morphological alteration, opening of the mitochondrial permeability transition pore (mPTP), cytochrome c release, mitochondria membrane potential depolarisation, caspase‐3 activation, Bax/Bcl‐2 imbalance and mitochondrial DNA damage (Qu et al., 2011, 2016) . In vitro studies, Liu et al. (2008) showed that 21 days of lycopene treatment (5 mg kg−1) suppresses Aβ1‐42‐induced activation of nuclear factor‐κB (NF‐κB), which ultimately results in the decrease in pro‐inflammatory cytokines, such as tumour necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β) and IL‐6, in different brain tissues, such as hippocampus, cerebral cortex and choroid plexus. In addition, 14 days of lycopene treatment at the doses of 1, 2 and 4 mg kg−1 has been shown to ameliorate learning and memory dysfunction in Aβ1‐42‐treated rats via inhibiting neuroinflammation (Sachdeva & Chopra, 2015). Research, Yu et al. (2017), showed that 8 weeks of lycopene treatment (5 mg kg−1) can reduce the increase in tau phosphorylation at Thr231, Ser235, Ser262 and Ser396 in brain tissues in P301 L transgenic mice, suggesting that inhibition of tau protein phosphorylation may mediate the anti‐AD effect of lycopene. As of today, however, the mechanism of the influence of lycopene on the tau phosphorylation is still unknown. Therefore, there is a need for research in this direction.

The case of Parkinson's disease showed that 7 days of lycopene treatment (20 mg kg−1) has been shown to suppress MPTP‐induced depletion of striatal dopamine in mice, suggesting that supplementation of lycopene or lycopene‐containing substances may help protect dopaminergic neurons against PD‐inducing stimuli (Prema et al., 2015). Reversal of MPTP‐induced dopamine decrease in the striatum by lycopene seems to be associated with the attenuation of oxidative stress because 7 days of lycopene treatment (20 mg kg−1) has been shown to decrease the levels of pro‐oxidative stress markers, such as 2‐thiobarbituric acid‐reactive substances (TBARS), and increase the level of GSH, a classical antioxidative stress marker (Prema et al., 2015). Further, 7 days of lycopene treatment (20 mg kg−1) has been shown to reduce MPTP‐induced increase in several apoptotic markers in mouse striatum, including Bax and caspase, suggesting that the anti‐PD effect of lycopene may be mediated by reducing neuronal apoptosis. However, how exactly lycopene inhibits neuronal apoptosis remains a perplexing question. Further research is needed to elucidate whether the antioxidative and antiapoptotic effect of lycopene in PD models is interconnected and whether regulation of neuroinflammatory response could contribute to the therapeutic effect of lycopene.

Effect of lycopene on the risk of skeletal system disease

Osteoporosis is one of the most common metabolic diseases of the osseous tissue, in the course of which – due to a growing advantage of bone resorption processes over bone formation processes – bone mass and strength are reduced, which exposes the patient to a higher risk of fractures (Manlogas & Parfitt, 2010). It is an old‐age condition that affects more women than men, particularly in the postmenopausal period due to lower oestrogen levels (Manolagas, 2010).

Research results published in recent years confirm‎ that in an ageing body, oxidative stress exacerbation boosts the pathogenesis of osteoporosis (Domazetovic et al., 2017). Among other things, it inhibits the formation of osteoblasts, shortens their lifespan and disturbs bone remodelling by diminishing the osteocyte pool. Also, excessive amounts of radicals exacerbate osteoclastogenesis (Almeida, 2012). According to Rivas et al. (2012), a lycopene‐rich diet may contribute to suppressing oxidative stress, limiting the negative effects of ROS on bone cells and inhibiting osteoporosis. Lycopene may affect the skeletal system by inhibiting osteoclastogenesis. At concentrations ranging from 10−8 to 10−5 m, lycopene stops osteoclastogenesis – both primary and parathormone‐stimulated – in murine femur marrow cultures. It also inhibits mineral resorption by osteoclasts cultivated on plates covered with tricalcium phosphate (Manlogas & Parfitt, 2010). Additionally, at a concentration of 10−5 m it stops the formation of osteoclasts secreting ROS (Rao et al., 2003). In human SaSO‐2 osteoblast‐like cells (from a cell line derived from osteosarcoma), lycopene at concentrations ranging from 10−6 to 10−5 m increases cell proliferation and boosts the activity of alkaline phosphatase in mature cells (Kim et al., 2003). In a 2007 study on murine osteoblasts first subjected to oxidative stress, lycopene (at concentrations ranging from 10−6 to 10−5 m) was observed to promote osteoblast proliferation and the mineralisation process, which was indicated by a growth in the number of bone grains (Zhang et al., 2007). Also, in a human osteoblast culture subjected to oxidative stress the application of lycopene has been shown to increase the area of the bone grains and decrease the production of ROS (Rao & Rao, 2013). In the 2012 research carried out by Liang et al.,2012 the application of lycopene (in the amounts of 20, 30 and 40 mg kg−1 of body weight for 8 weeks) prevented the development of osteoporosis induced by oestrogen deficiency in 3‐month‐old rats in a dose‐dependent manner. Both the mineral content and density of the femur grew, and its mechanical properties improved. Under the effects of lycopene, interleukin‐6 concentration dropped, and serum oestrogen levels increased. A similar protective effect of lycopene on murine osseous tissue was observed by Yang et al. in 2012, who applied lycopene in doses of 10 or 20 mg kg−1 of body weight for 12 weeks in 6‐month‐old rats. In a dose‐dependent manner, lycopene increased the mineral density and strength of the femur and elevated the serum concentrations of calcium and phosphates. Additionally, some histomorphometric properties improved, and the level of oestradiol demonstrated a statistically significant growth. In 2006, experiments on an Italian population of women focus on serum lycopene concentrations, and lower lycopene levels were shown to exist in patients with severe osteoporosis than in healthy study subjects (Maggio et al., 2006). Similarly, American postmenopausal women with osteoporosis have been demonstrated to exhibit lower serum lycopene levels than healthy individuals (Yang et al., 2008). Population studies carried out within the framework of the Framingham Osteoporosis Study project have confirmed the beneficial effects of lycopene consumption on bone mineral density in women and a lower frequency of hip fractures and osteoporotic nonvertebral fractures in elderly (both female and male) patients (Sahni et al., 2009). Moreover, Rao et al. (2007) have shown that serum concentrations of lycopene (74.99 ± 15.09–502.8 ± 47.39 nm) grow proportionally to its dietary supply (1.76 ± 0.76–7.35 ± 0.80 mg day−1). Persons consuming larger quantities of lycopene have been observed to have lower concentrations of NTx (type I collagen cross‐linked N‐telopeptide) – a bone resorption marker, while no significant reduction in alkaline phosphatase activity has been seen. Higher blood lycopene levels have been shown to be associated with the limitation of protein oxidation. Research results confirm‎ that lycopene has an inhibitory effect on bone resorption in postmenopausal women. A study carried out by Mackinnon et al.2011 in 2011 claimed that apart from increasing the activity of glutathione peroxidase and reducing the activity of catalase, avoiding the consumption of lycopene also caused a significant increase in NTx levels, without affecting the activity of alkaline phosphatase. Thus, such data give an indirect indication of lycopene's possible inhibitory effect on bone resorption. In the studies carried out by Ardawi Mohammed‐Salleh et al. (2016), the effects of lycopene treatment on postmenopausal osteoporosis were eval‎uated on 6‐month‐old female rats. Six‐month‐old female Wistar rats (n = 264) were sham‐operated (SHAM) or ovariectomised (OVX). The SHAM group received oral vehicle only, and the OVX rats were randomised into five groups receiving oral daily lycopene treatment (mg/kg body weight per day): 0 OVX (control), 15 OVX, 30 OVX and 45 OVX, and one group receiving alendronate (ALN) (2 μg/kg body weight per day), for 12 weeks. Bone densitometry measurements, bone turnover markers, biomechanical testing and histomorphometric analysis were conducted. Microcomputed tomography was also used to eval‎uate changes in microarchitecture. According to the authors, lycopene treatment suppressed the OVX‐induced increase in bone turnover, as indicated by changes in biomarkers of bone metabolism: serum osteocalcin (s‐OC), serum N‐terminal propeptide of type 1 collagen (s‐PINP), serum cross‐linked carboxyterminal telopeptides (s‐CTX‐1) and urinary deoxypyridinoline (u‐DPD). Significant improvement in OVX‐induced loss of bone mass, bone strength and microarchitectural deterioration was observed in lycopene‐treated OVX animals. These effects were observed mainly at sites rich in trabecular bone, with less effect in cortical bone. Lycopene treatment down‐regulated osteoclast differentiation concurrent with up‐regulating osteoblast together with glutathione peroxidase (GPx) catalase (CAT) and superoxide dismutase (SOD) activities. These findings demonstrate that lycopene treatment in OVX rats primarily suppressed bone turnover to restore bone strength and microarchitecture.

Although it is too early to suggest that eating tomatoes and tomato products will prevent osteoporosis, it would be a healthy practice to include tomatoes and tomato products in the diet as a source of lycopene for the prevention of oxidative stress‐related chronic diseases, including osteoporosis. The final results of our study may indicate that lycopene can be used either as a dietary alternative to drug therapy or as a complement to drugs used in women at risk of osteoporosis.

Conclusions

In this paper, a review of state‐of‐the‐art reports on lycopene and its health effects has been presented. Due to its distinctive ability to neutralise free radicals, lycopene is believed to confer measurable protection against cancer, cardiovascular disease and some inflammatory diseases. The multiple biological effects of lycopene are predetermined by the unique chemical structure of the compound and its particular physicochemical properties. Promising data from epidemiologic as well as cell culture and animals studied suggest that lycopene and the consumption of lycopene‐containing food may affect several chronic disorders. Nevertheless, more clinical data are needed to support this hypothesis. In addition, further detailed research is required to understand other beneficial health effects of lycopene and its mechanisms, particularly in neuroprotective diseases. The research presented in the article showed that lycopene, despite low bioavailability, can exert prophylactic and/or therapeutic effects in different disorders via antioxidative, anti‐inflammatory and antiproliferative activities. The results of work on animals and on humans suggest that the consumption of lycopene in food or by itself may reduce cancer risk. Lycopene may have a protective effect in cancer, especially in PCa. It is also assumed based on research that is not always unequivocal that it may reduce the risk of cardiovascular disorders. From the data presented, lycopene and tomato products seem to possess direct hypocholesterolaemic properties; however, further studies are required to gain a better understanding of the role of lycopene in regulation of cholesterol metabolism. Future research should focus on interactions of lycopene with Rother carotenoids. It is quite likely that lycopene acts with other tomato carotenoids to exert its biological activity. An improved understanding of lycopene metabolism and the biological significance/functions of its different isomers and metabolites is also critical to elucidate mechanisms, whereby this compound may exert hypocholesterolaemic effects. Lycopene supplementation decreases oxidative stress and exhibits beneficial effects on bone health, but the mechanisms through which it alters bone metabolism in vivo remain unclear. Treatment with lycopene decreases differentiation of osteoclasts with osteoblast increasing activity due to catalase (GPx) activity of glutathione peroxidase (CAT) and superoxide dismutase (SOD). These findings show that treatment with lycopene in OVX rats primarily suppressed bone turnover to restore bone strength and microarchitecture. Therefore, further research is needed on humans to confirm‎ the usefulness of lycopene as an osteoprotective agent. It is also believed that lycopene may have neuroprotective effects in the central nervous system (CUK). Among other things, it is stated that lycopene supplementation may improve cognitive performance in Tau transgenic mice after expressing the P301L mutation and alleviate β‐amyloid‐induced cell toxicity (Aβ) in cultured neurons. In the model of Parkinson's disease (PD) induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), lycopene reverses the motor abnormalities of mice. It can be assumed that the neuroprotective properties of lycopene can be used in the future in the prevention of neurodegenerative diseases. As of today, there is a need for further research in this direction, because there is no golden mean for Alzheimer's (AD) or Parkinson's (PD) disease.