Biologically Active Phytochemicals in Human Health: Lycopene

Abstract

Dietary guidelines around the world recommend increased consumption of plant foods to combat chronic diseases such as cancer, cardiovascular diseases, diabetes, and osteoporosis. These plant foods (fruits, vegetables, cereals, and legumes) contain many beneficial phytochemicals. Oxidative stress, caused by the production of highly reactive oxygen species (ROS), has received a great deal of interest in recent years. Antioxidants, including lycopene, by virtue of their ability to interact with ROS, can mitigate their damaging effect and play a significant role in the prevention of chronic diseases. Several mechanisms have been proposed to explain the beneficial effects of these phytochemicals in human health. In this article, we focus on lycopene and its role in human health. We also discuss its chemical properties, the dietary sources of lycopene, its bioavailability, and the mechanisms of action in disease prevention.

Keywords:

• Phytochemicals
• Lycopene
• Human health
• Chronic diseases

INTRODUCTION

Dietary guidelines around the world recommend increased consumption of plant foods to combat chronic diseases such as cancer, cardiovascular diseases, diabetes, and osteoporosis. Plant foods that include fruits, vegetables, cereals, and legumes contain many beneficial phytochemicals (Table 1). Several mechanisms have been proposed to explain the beneficial effects of these phytochemicals in human health (Table 2). Oxidative stress, as an important etiological factor in the causation of chronic diseases, has received great deal of interest in recent years.[1–8] Oxidative stress is caused by the production of highly reactive oxygen species (ROS) that cause oxidative damage to important cellular biomolecules such as the lipids, proteins and DNA.[9] When unrepaired they can accumulate in the cell and lead to increased risk of chronic diseases (Fig. 1). ROS are produced endogenously as by-products of normal metabolic processes, as well as through life style factors such as diet, smoking, and exercise.[10] Antioxidants, by virtue of their ability to interact with ROS, can mitigate their damaging effect and play a significant role in the prevention of chronic diseases.[9] The main sources of antioxidants in plants include vitamins (C, E, and A), minerals (selenium), and phytochemicals (polyphenols, carotenoids). We focus on lycopene and its role in human health in this article.

Figure 1 Oxidative stress, antioxidants, and chronic diseases.

Table 1 Plant phytochemicals beneficial to human health.

Carotenoids (β-Carotene, Lycopene)

Terpenoids (Saponins)

Phytosterols

Flavonoids

Indoles

Isoflavones

Isothiocyanates

Lignan

Phytate

Fiber (soluble & insoluble/gelling & viscous)

Table 2 Mechanisms of biological action of phytochemicals.

Oxidative stress

Gene function regulation

Gap-junction communication

Hormone and immune modulation

Carcinogen metabolism

Metabolic pathway — induction of phase II enzymes

CHEMICAL PROPERTIES AND DIETARY SOURCES OF LYCOPENE

Lycopene, a lipid soluble carotenoid antioxidant, is synthesized by many plants and microorganisms but not by animals and human.[11] It is a highly unsaturated open straight chain hydrocarbon consisting of 11 conjugated and 2 unconjugated double bonds.[9,12,13] It is responsible for the red color of many fruits and vegetables such as the tomatoes. Unlike some other carotenoids, lycopene lacks the terminal β-ionic ring in its structure and provitamin A activity. In nature, lycopene is present primarily in the all trans isomeric forms.[14] However, it can undergo mono-or poly-isomerization by light, thermal energy, and chemical reactions to its cis-isomeric forms (Fig. 2). It is a highly stable molecule, however, it can undergo oxidative, thermal, and photodegradation.[10] Studies have shown that lycopene remains stable under the conditions of thermal processing and storage.[15] A recent publication showed that 5-cis lycopene is the most stable isomer followed by the all-trans, 9-cis, 13-cis, 15-cis, 7-cis, and 11-cis. 5-cis lycopene has also been shown to have the highest antioxidant properties followed by 9-cis, 7-cis, 13-cis, 11-cis, and the all-trans isomers.[16]

Figure 2 All trans and cis-isomeric forms of lycopene.

Common dietary sources of lycopene include tomatoes, watermelon, pink guava, pink grape fruit, papaya, apricot and other fruits (Table 3). Tomatoes and tomato-based foods account for more than 85% of all the dietary sources of lycopene.[17] Lycopene content of some common tomato-based foods is shown in Table 4.[9,18]

Table 3 Lycopene content of common fruits and vegetables.

Fruits and vegetables	Lycopene (μg/g wet weight)
Tomatoes	8.8–42.0
Watermelon	23.0–72.0
Pink guava	54.0
Pink grapefruit	33.6
Papaya	20.0–53.0
Apricot	<0.1

Table 4 Lycopene content of common tomato based foods.

Tomato products	Lycopene (μg/g wet weight)
Fresh tomatoes	8.8–42.0
Cooked tomatoes	37.0
Tomato sauce	62.0
Tomato paste	54.0–1500.0
Tomato soup (condensed)	79.9
Tomato powder	1126.3–1264.9
Tomato juice	50.0–116.0
Pizza sauce	127.1
Ketchup	99.0–134.4

BIOAVAILABILITY OF LYCOPENE

Lycopene levels in body fluids and tissues have been used to estimate the absorption of lycopene from dietary sources. Lycopene is present in plant foods bound to the cellular matrix. Disruption of such cellular matrix, as achieved during food preparation and processing, can facilitate its release and enhance absorption. Since lycopene is a fat-soluble compound, the presence of lipids can also facilitate its absorption. The majority of the fat soluble compounds, including lycopene, are absorbed across the gastrointestinal tract via a common chylomicrons mediated mechanism.[19] The presence of other fat-soluble compounds can, therefore, also influence the lycopene absorption.

In general, lycopene absorption in humans from dietary sources is reported to be in the range of 10–30%.[18,20] When subjects consumed tomato juice, tomato sauce and tomato oleoresin in the form of capsules for one week, serum lycopene levels were shown to be significantly higher than controls.[21] Other studies have shown that lycopene is absorbed more efficiently from processed tomato products compared to raw tomatoes.[20,22] The increased absorption of lycopene from processed tomato products is attributed to the presence of cis-isomers of lycopene.[20]

Upon absorption, lycopene is distributed throughout the body. Testes, adrenal glands, prostate, breast, and liver were shown to have the highest levels of lycopene in humans.[9,23] Lycopene in the tissues undergoes oxidation and metabolism. Several oxidized forms of lycopene and polar metabolites have recently been isolated and identified.[12] The biological significance of these findings is not clear at present and is the subject of many studies.

MECHANISMS OF ACTION OF LYCOPENE

Due to the highly unsaturated nature of the lycopene molecule, its antioxidant properties have been the main focus of research to study its biological role. However, other studies are now showing that lycopene may also provide a protective effect against chronic diseases via other mechanisms.[24,25] These other mechanisms include gene function regulation, gap-junction communication, hormone and immune modulation, carcinogen metabolism, and metabolic pathways involving phase II drug-metabolizing enzymes.[26] An extensive review on both the antioxidant mechanisms and other molecular mechanisms has recently been published.[9]

DAILY INTAKE LEVELS AND RECOMMENDED LEVELS OF LYCOPENE

Estimation of the daily intake levels of lycopene has been difficult due to the variability in the reported levels of lycopene in food sources and reporting of food intake records. Reported daily Intake levels range from 3.7 to 16.2 mg in the United States of America, 25.2 mg in Canada, 1.3 mg in Germany, 1.1 mg in United Kingdom, and 0.7 mg in Finland.[27] Close to 50% of the population in North America are estimated to consume 1.9 mg of lycopene per day or even less. Scientists agree that the average intake levels of lycopene are not high enough to provide beneficial effects. Lycopene has not yet been recognized as an essential nutrient, therefore, there is no official recommended daily intake (RDI) level set by health professionals and government regulatory agencies. However, based on reported studies, a level of 30–35 mg has been suggested initially.[27] More recent studies have shown that a daily intake level of 5–7 mg in normal healthy human beings is sufficient to maintain the circulating levels of lycopene at levels sufficient to combat oxidative stress and to prevent chronic diseases.[28] With diseases such as cancer and cardiovascular diseases, higher levels of lycopene—ranging from 35–75 mg per day—may be required.[29]

LYCOPENE AND CHRONIC DISEASES

The in-vitro antioxidant effects of lycopene have been known for a long time. Its biological role in the prevention of chronic diseases, however, has been studied more recently. According to the basic hypothesis underlying these studies, the accumulation of ROS—either due to higher levels of ROS produced as a result of lifestyle activities or due to the state and nature of disease and impaired repair mechanisms—can lead to the oxidation of critical cellular biomolecules and eventually to an increased risk of chronic diseases. Antioxidants, such as lycopene, can interact with ROS at an early stage and prevent the cellular oxidation, which can either delay or prevent the progression of human diseases. The evidence to date for the beneficial role of lycopene in human diseases comes primarily from epidemiological studies. However, tissue culture studies utilizing several human cancer cell lines and animal studies have also been reported in the literature.[18] Human clinical trials are now being undertaken increasingly to evaluate the role of lycopene in several human diseases.

In 1995, Giovannucci et al. showed an inverse correlation between the consumption of tomatoes and the risk of prostate cancer.[30] This effect was shown to be more significant with increased aggressiveness of the disease. The authors suggested that lycopene is possibly the compound present in tomatoes responsible for the beneficial effect. A follow up publication in 1999[31] evaluated 72 studies that were reported on the role of lycopene in human cancers. This meta-analysis study showed that lycopene intake, as well as serum lycopene levels, were inversely related to several cancers including prostate, breast, cervical, ovarian, liver, and other organ sites.

Since the publication of these studies several other studies have been undertaken.[32,33] A great majority of the studies demonstrated that with increased intake of lycopene, the serum levels of lycopene increased and significantly reduced the risk of cancers. In 1998, Rao and Agarwal provided answers to the question of lycopene bioavailability and its in-vivo antioxidant properties.[21] This study showed that lycopene could be absorbed quite readily from different dietary sources of lycopene and once absorbed the antioxidant properties were maintained. Measuring the serum lycopene levels and also biomarkers of lipid, protein, and DNA oxidation showed this. As the levels of serum lycopene increased, the oxidation of lipid, proteins and DNA decreased significantly. Although the epidemiological studies have provided convincing evidence in support of the protective role of lycopene in cancer, the status of oxidative stress and lycopene in cancer patients was unknown. In a recent case-control study, the status of oxidative stress and antioxidants in prostate cancer patients were assessed and compared against age-matched control subjects.[17] Results showed remarkable differences in levels of serum carotenoids, biomarkers of oxidation and prostate specific antigen (PSA) levels in these subjects. Although there were no differences in the levels of β-carotene, lutein, cryptoxanthin, vitamin E and A between the cancer patients and their controls, the levels of lycopene were significantly lower in the cancer patients. As expected, the PSA levels were significantly elevated in the cancer patients, who also had higher levels of lipid and protein oxidation, indicating higher levels of oxidative stress in cancer patients. To explain the observed results, the authors suggested that either impaired absorption of lycopene by the cancer patients or the increased utilization of lycopene could be responsible for the lower levels. A follow up pharmacokinetic study with the prostate cancer and age-matched controls raised the possibility of impaired absorption of lycopene in the case of cancer patients since the absorption slopes were significantly lower in these patients compared to their controls. This area is the subject of scientific studies at present.[27]

Overall, epidemiological studies, in-vitro tissue culture studies, animal studies and now some human intervention studies are showing that increased intake of lycopene will result in increased circulatory and tissue levels of lycopene. In-vivo lycopene can act as a potent antioxidant and protect cells against oxidative damage and thereby prevent or reduce the risk of several cancers. In a more recently reported study, lycopene was shown to decrease the levels of PSA as well as the growth of prostate cancer in newly diagnosed prostate cancer patients receiving 15 mg of lycopene daily for 3 weeks prior to radical prostactomy.[29,34,35] Although small in number, these observations raise the possibility that lycopene may be involved not only in the prevention of cancers but may also play a role in the treatment of the disease. Further studies are needed to get additional proof and to gain better understanding of the mechanisms involved.

Although cancer and prostate cancer in particular has been the focus of most of the research so far relating to lycopene, cardiovascular disease, another major cause of human mortality, is also being investigated. Several reports have now appeared in the literature in support of the role of lycopene in the prevention of CVD. The strongest population-based evidence comes from a multicenter case-control study (EURAMIC) that evaluated the relationship between adipose tissue antioxidant status and acute myocardial infarction.[36,37] Subjects that included 662 cases and 717 controls were recruited from ten different European countries. Results of this study showed a dose-response relationship between adipose tissue lycopene and the risk of myocardial infarction. Another study that compared the Lithuanian and Swedish populations showed lower lycopene levels to be associated with increased risk and mortality from coronary heart disease (CHD).[38] Lycopene has also been shown to significantly reduce the levels of oxidized LDL (LDL_ox) that is considered to be a risk factor for CVD.[39] In another small study, lycopene was shown to reduce the serum total cholesterol levels and thereby lowering the risk of CVD.[40]

In addition to cancers and CVD, studies are now evaluating the role of lycopene in other human diseases. A recent study from Israel showed that lycopene decreased the systolic and diastolic blood pressures when mildly hypertensive subjects were given lycopene.[41] In another study from India, infertile men who were given lycopene supplementation significantly improved the quality of their seminal fluid showing increased sperm density and motility.[42] An investigator in Canada is now studying the role of lycopene in the prevention of osteoporosis.[9] Tissue culture studies with osteoclasts and osteoblasts incubated in different physiologically relevant concentrations of lycopene showed activation of the bone forming osteoblasts and a reduction in the activity of bone desorbing osteocalsts.[9,43,44] Based on these positive results, the author is now undertaking human clinical studies. Levels of antioxidants including lycopene, biomarkers of oxidation, and bone turnover were measured in a group of postmenopausal females who are at risk for osteoporosis. An inverse relationship was observed between the intake and serum levels of lycopene and bone turnover markers. This effect was attributed to the antioxidant property of lycopene. The authors are now undertaking a dietary intervention study to evaluate the effect of lycopene dose and modality of lycopene intake on the risk of osteoporosis. Another recent review article has elaborated on the possible role of lycopene in neurodegenerative diseases including Alzheimer's disease.[45] The authors argued that human brain represents a vulnerable organ for oxidative damage due to its high levels of oxygen uptake and utilization. The evidence was presented to show a causal relationship of oxidative stress to the damage of the central nervous system. At a recent conference on the role of processed tomatoes in human health, evidence was provided for the protective role of lycopene in the prevention of emphysema in a Japanese population.[46] Undoubtedly, future research will also explore the role of lycopene in other inflammatory and metabolic diseases. Lycopene is also finding newer applications as an antioxidant component of pharmaceutical, nutraceutrical, and cosmoceutical products.

The quest for studying the role of many human diseases underlines the common etiological and mechanistic nature of these diseases. It would seem that oxidation of cellular components as an initial event can eventually lead to the incidence of several diseases. Oxidation of LDL has been shown to be involved in increasing the risk of CVD. Similarly, oxidation of DNA has been identified as an early step in the progression of cancers. Protein oxidation can also alter the activity of several metabolic enzymes and thereby influence many disease conditions. Lycopene by acting as an antioxidant can prevent the disease progression at an early stage and improve the quality of life.

SUMMARY AND FUTURE DIRECTIONS

Historically, lycopene has been known to posses antioxidant properties. Its biological role in the prevention and perhaps in the treatment of human chronic diseases is now being studied and understood. Although the naturally present all-trans lycopene is absorbed, studies have shown that thermal processing of tomato products can enhance the cis-lycopene levels significantly and improve its bioavailability. Other biological significances of the isomerization of lycopene and its metabolites are not yet fully understood. There is compelling evidence to support the role of lycopene in the prevention of cancer and CVD. Newer evidence is beginning to be reported for other diseases such as hypertension, osteoporosis, and asthma. Although the antioxidant property of lycopene has been mentioned as the primary mechanism for the biological activity of lycopene, newer evidence indicates other mechanisms as well. It is important to note that humans do not synthesize lycopene, and they are entirely dependent on dietary sources to meet their daily intake requirements of lycopene. There is a big gap between the suggested/recommended levels of daily intake of lycopene and the actual average daily intakes in the world (Fig. 3).

Figure 3 Intake vs. recommended levels of lycopene.

An ample opportunity exists to narrow this gap and perhaps to eliminate it completely. This will not only involve to increase the dietary intake of lycopene but also to understand its mechanisms of action in disease prevention. Future studies should, therefore, address the bioavailability, metabolism, mechanisms of action, and safety of lycopene for it to be a major phytochemical involved in the prevention of human diseases and improvement in quality of life.