Abstract
Oxidative stress induced by highly reactive oxygen species (hROS) is recognized as an important mechanism in the causation of chronic diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of several antioxidants including lycopene, of recent interest and available in the diet primarily from tomatoes and tomato products. Popular for its role in prostate health, lycopene also improves markers for and risk of multiple cancers, cardiovascular disease, osteoporosis, diabetes, hypertension, male infertility and macular degeneration. Epidemiological, tissue culture, animal and human studies show a beneficial role for lycopene in the prevention and possibly treatment of chronic diseases. Generally, lycopene intake of North Americans is low (≤1.86 mg/day) compared to 7 mg/day now recommended to maintain circulatory lycopene at levels consistent with providing beneficial effects. Ongoing and future research is warranted to increase our understanding of lycopene’s role in human diseases, its mechanisms of action and its use in the management of public health.
Lycopene has attracted attention for nearly 50 years for its biochemical and physiochemical properties.(1-4) Since that time, epidemiological, in vitro, and in vivo animal and human experiments have provided support for lycopene’s antioxidant health benefits and its potential to reduce the risk of several cancers and cardiovascular disease (CVD). Lycopene is a natural pigment synthesized by plants and microorganisms,(4) and the diet constitutes the primary source of lycopene for humans. The attractive red color of tomatoes is due to the presence of lycopene; this antioxidant carotenoid can also be found in watermelon, pink grapefruit, apricots and pink guava.(4) Lycopene is an acyclic, highly unsaturated, straight chain hydrocarbon containing 13 double bonds (11 conjugated, 2 non-conjugated).(4) Lycopene is an isomer of beta-carotene but does not have provitamin A activity.(3) Oxygen-derived free radicals known as reactive oxygen species (ROS) are generated endogenously through normal metabolic activity, lifestyle activities, and diet. ROS-related oxidative stress results in the damage of cellular components including lipids, proteins and DNA. Cellular damage and oxidation of cellular biomolecules has been implicated in the early stages and pathogenesis of various human chronic diseases.(5-12) In contrast, lycopene is a potent antioxidant that provides protection against cellular damage caused by ROS13 and, therefore, may play an important role in disease prevention. More specifically, because of its high number of conjugated double bonds, lycopene exhibits higher (two and ten times) singlet oxygen quenching ability compared with beta-carotene and alphatocopherol, respectively.(13)
Lycopene: Bioavailability and Isomerization
In human dietary intervention research, serum lycopene levels significantly increase after consuming tomato foods or lycopene supplementation.(14,15) However, not all sources of lycopene are equally bioavailable. Ingested in its natural trans form, such as is prominent in tomatoes, lycopene is poorly absorbed(4) whereas heat processing of tomatoes and tomato products induces isomerization of lycopene from all-trans to cis configuration in turn increasing its bioavailability.(16-18) Remaining to be determined, however, is whether or not cisisomers are biologically more effective than trans-isomers once in the body.(4)
In addition to the importance of its conformation at the time of ingestion, bioavailability of lycopene is also affected by the presence of lipids(17,18) due to its fat-soluble nature. The presence of other carotenoids, such as beta-carotene that share a common LDL-mediated absorption pathway, can also influence lycopene absorption.19 Within tomato products, lycopene is most prominent making up 60% to 64% of the carotenoids present. Other phytonutrients such as phytoene (10% to 11%), gamma-carotene (10% to 11%), neurosporine (7% to 9%), phytofluene (4% to 5%), betacarotene (1% to 2%), delta-carotene (1% to 2%) and lutein (trace to 1%)(18) are also present in tomatoes and tomato products. Recent studies have shown lycopene to act synergistically with these phytonutrients in providing its beneficial properties.
In human plasma, total lycopene is an isomeric mixture containing 40% to 50% as cis isomers. The relative stabilities of the most commonly identified lycopene isomers, from most stable to least, are 5-cis, all-trans, 9-cis, 13-cis, 15-cis, 7-cis, and 11-cis. The relative antioxidant properties of these same lycopene isomers as indicated by their ionization potential from greatest to least, are 5-cis, 9-cis, 7-cis, 13-cis, 15-cis, 11- cis and all-trans.(20)
Lycopene: Biological Action
In vitro and cell culture studies have demonstrated several biological actions of lycopene. These actions include: protection against LDL oxidation, inhibition of HMG-CoA reductase activity resulting in a reduction in native cholesterol, protection of lymphocytes against membrane damage and cell death, reduction of cancer cell proliferation induced by IGF-1, synergistic inhibition of an androgen-dependent prostate cancer cell line when in combination with alpha-tocopherol, inhibition of leukocyte cell-cycle progression, induction of cell differentiation when in combination with other nutrients such as vitamin D3, and upregulation of gap-junction communication.(4)
Similarly, several trials in healthy men and women have demonstrated the ability for a variety of doses of dietary lycopene (5 to 150 mg/day) from foods and tomato oleoresin extract to exert a positive significant influence on serum biomarkers considered to relate to atherogenesis and cancer risk.(15,21,25) These effects include decreased serum lipid peroxidation,(14,15,21,22) decreased serum LDL oxidation,(14,21,22) and decreased protein oxidation.(14,22) Human research has also shown lycopene supplementation to result in significantly increased total antioxidant potential(14) and a trend toward decreased serum DNA oxidation.(15)
Lycopene and Cancer
With respect to lycopene’s role in the prevention of cancer, Giovannucci(23) reviewed 72 epidemiological studies and found the consumption of tomatoes and tomato products or circulating levels of lycopene to be inversely related to risk of cancers, most prominently, cancers of the prostate gland, lung, and stomach. The results from this study, which examined case-control dietary studies, prospective dietary studies and blood specimen-based investigations, also suggested a reduced risk of other cancers, including pancreatic, colorectal, esophageal, oral, breast, and cervical cancers.(23) Other cancers investigated did not show clear relationships to the intake of tomato, tomato products or lycopene.(23) Another recent meta-analysis of observational studies(24) looked at 11 case-control and 10 cohort studies to determine the effect produced by a daily intake of tomato products. It was concluded that tomato products can play a role in the prevention of prostate cancer. However, the beneficial effect of consuming tomato products was found to be modest and restricted to high amounts of intake. In research examining prostate cancer more specifically, a case-control study of prostate cancer patients found serum and prostate tissue lycopene levels to be significantly lower in cancer patients when compared with their agematched controls.(25) These findings suggest that prostate cancer patients either lack the ability to absorb lycopene efficiently or utilize lycopene rapidly due to increased oxidative stress. This case-control study also revealed significantly higher serum prostate specific antigen (PSA) (r=0.55; P=0.006) and protein oxidation in prostate cancer patients compared with controls.(25) No significant relationship was observed between serum beta-carotene and serum PSA (r=0.24; P=0.253) in prostate cancer cases compared with controls.(25) Finally, a recent study with prostate cancer patients has shown a possible prophylactic effect of lycopene in the shrinkage and regression of prostate tumors.(26,27) This area of lycopene research needs to be studied further in the future.
Lycopene and Cardiovascular Disease
In addition to cancer and lycopene, another area of promising research is that of lycopene and cardiovascular disease (CVD). In general, epidemiological studies exploring lycopene and CVD show significant inverse associations between the intake of tomatoes and serum, plasma, and adipose tissue levels of lycopene. However, some studies have failed to show such associations.
In a large multicenter case-control study (EURAMIC), the relationship between adipose tissue antioxidant status (alpha- and beta-carotene and lycopene) and acute myocardial infarction were evaluated in 662 cases and 717 controls.(28) Subjects in this trial were recruited from 10 European countries to maximize the variability in exposure within the study.(28) Adipose antioxidant levels were measured because they are considered to be a better marker of long-term exposure than serum lycopene.(28) After adjusting for a range of dietary variables, higher lycopene but not alpha- or beta-carotene adipose tissue levels were found to be protective against myocardial infarction risk in non-smokers (OR=0.52, P=0.005; OR=0.91, P=0.66; and OR=1.01, P=0.96; respectively).28 Also related to cardiovascular disease, mildly hypercholesterolemic men and women with grade-1 hypertension taking 15 mg/day of lycopene from tomato oleoresin antioxidant-rich tomato extract had significantly decreased systolic and diastolic blood pressure compared to placebo.(29)
Lycopene and Bone Health
Recently, lycopene research has begun to explore the potential for this antioxidant carotenoid to work against the onset of bone disease. Although not fully understood, there is evidence that oxidative stress caused by ROS is associated with the pathogenesis of osteoporosis. In a recent in vitro study of bone marrow prepared from rat femurs, it was demonstrated that lycopene, in the absence or presence of parathyroid hormone (PTH), inhibited osteoclastic mineral resorption and formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated osteoclasts, as well as the ROS produced by osteoclasts.(30) The authors suggested that this finding may be important in the pathogenesis, treatment and prevention of osteoporosis.(30)
Clinical studies are now being conducted to study the role of lycopene in osteoporosis.(31) Researchers have studied the relationship between lycopene and bone resorption as measured by serum N-telopeptides of type I collagen (NTx) in postmenopausal women. They found higher lycopene intake and higher serum lycopene to be associated with lower bone resorption (p<0.005).31 Based on the results from this study, the researchers are now conducting a lycopene intervention study with postmenopausal females to evaluate the relationship between lycopene and the risk of osteoporosis.
Lycopene and Male Infertility
An area of concern for many men is that of infertility. Infertile men genetically tend to produce higher levels of free radicals. Ongoing research in India is exploring this relationship and the influence of supplementing with lycopene. In one study of 50 volunteers with low active sperm counts, 35 volunteers (70%) experienced an improvement in sperm count, 30 (60%) had improved functional sperm concentrations, 27 (54%) had improved sperm motility, 23 (46%) had improved sperm motility index, and 19 (38%) had improved sperm morphology following consumption of 8 mg/day of lycopene supplementation from tomato oleoresin extract.(32) Further studies are now being undertaken to confirm these preliminary observations and to gain further understanding into the role of lycopene in male infertility.
Recommended Lycopene Intakes
Average daily intake levels of lycopene range from 0.70 to 25.20 mg/day but 50% of North Americans consume < 1.86 mg/day of lycopene. Based on human research,(22) recent recommendations for the daily intake of lycopene suggest 7 mg/day. At this level of intake, circulatory lycopene concentration is maintained at a level consistent with that shown to reduce lipid peroxidation and to result in other beneficial effects of lycopene.
Health Claims Associated with Lycopene
Emphasizing consumption of fruits and vegetables is part of the dietary guidelines recommended for the prevention of chronic diseases.33 Dietary benefits generally associated with increased plant food consumption include lower intakes of energy and fat, and higher intakes of fiber and micronutrients including phytochemicals such as lycopene but also phytosterols, flavonoids, indoles, isoflavones, isothiocyanates, lignans, phytates, soluble and insoluble fibers, terpenoids (saponins) and other carotenoids. The FDA has approved Generally Recognized as Safe (GRAS) status to lycopene. Recently, the FDA has also given a limited health claim declaration for lycopene, stating “Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer.” However, FDA concludes that the evidence in support of lycopene in prostate cancer risk reduction is still not very strong and needs further research.
Conclusion
There is convincing evidence to suggest a causal link between oxidative stress and human chronic diseases. Antioxidants have been suggested as playing an important role in protecting cells and cellular components against oxidative damage. Lycopene is a potent antioxidant carotenoid present in tomatoes, tomato products and other fruits. However, it is not synthesized by animals and humans. Dietary sources and nutritional supplements constitute the major source of lycopene intake. The evidence in support of the role of lycopene in the prevention of chronic diseases is primarily epidemiological in nature up to this stage. However, tissue culture, animal experiments and more recently human intervention studies are providing convincing evidence in support of the epidemiological observations. Although the antioxidant properties of lycopene are considered to drive the major mechanism by which lycopene provides beneficial effects, other mechanisms are also being suggested. A daily intake of 7 mg of lycopene is currently recommended to maintain the circulatory levels of lycopene consistent with reduction in lipid peroxidation. Recent studies also suggest synergistic interactions between lycopene and other phytonutrients in tomatoes and tomato products leading to its beneficial effects. Future research addressing the bioavailability of lycopene, its mechanisms of action and its role in other important human chronic diseases is needed to fully understand the role of lycopene in human health and to take advantage of this important ‘nutraceutical’ product in the management of chronic diseases.
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