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Lycopene

Scientific Name(s): Psi-carotene, Psi
Common Name(s): Lycopene

Clinical Overview

Use

Scientific literature documents lycopene’s antioxidant activity and its use in cancer prevention (breast and prostate), as well as its use in the prevention of cardiovascular disease.

Dosing

Lycopene administered as a pure compound has been studied in clinical trials at dosages of 7 to 75 mg/day. Lycopene is primarily available in capsule and softgel form, with dosage guidelines from manufacturers ranging from 10 to 30 mg taken twice daily with meals. Lycopene is also incorporated in multivitamin and multimineral products.

Contraindications

Avoid with hypersensitivity to lycopene or to any of its food sources, especially tomatoes. Tomato-based products are acidic and may irritate stomach ulcers.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. The amount of lycopene in food is assumed to be safe. Tomato consumption increases lycopene concentration in the breast milk and plasma of lactating women.

Interactions

None well documented.

Adverse Reactions

In general, tomato-based products and lycopene supplements are well tolerated. Some GI complaints (eg, diarrhea, dyspepsia, gas, nausea, vomiting) are documented. One trial reported a cancer-related hemorrhage in a patient taking lycopene, but causality was unclear.

Toxicology

None known.

Botany

Lycopene is a common carotenoid compound found in fruits, vegetables, and green plants.1 It is responsible for a red plant pigment found primarily in tomatoes. Other sources include apricots, cranberries, grapes, pink grapefruits, guavas, papayas, peaches, and watermelons.2

History

In North America, nearly 85% of dietary lycopene is derived from tomatoes and tomato-based products.1 Tomatoes have been cultivated since the 16th century as a food source. In some countries, the tomato was thought to be poisonous and used for decorative purposes only. Christopher Columbus may have learned of the nutritional benefits of fruits and tomatoes from the inhabitants of the New World.3 There is a large body of evidence documenting the health benefits of lycopene, as well as its biological activity in numerous human diseases.1, 2, 3

Chemistry

Lycopene is a 40-carbon acyclic carotenoid containing 11 conjugated double bonds, with a molecular mass of 536.2, 4, 5 It consists of only hydrogen and carbon atoms, and is 1 of 600 carotenoids synthesized by plants and photosynthetic microorganisms.2, 4 The biochemistry of lycopene is unique because it has no pro-vitamin A activity, unlike many other carotenoids, such as alpha-carotene and beta-carotene. Lycopene is lipophilic and insoluble in water. It is the most abundant carotenoid in tomatoes (0.9 to 4.2 mg per 100 g), followed by beta-carotene, gamma-carotene, phytoene, and other minor carotenoids,4 and is touted as the highest overall single oxygen-quenching carotenoid, with double the value of beta-carotene.6

Lycopene is relatively resistant to heat-induced geometrical isomerization in tomato processing.7 Processed tomato products are a better source of lycopene than fresh tomatoes,8 with lycopene more bioavailable.9 In addition, human uptake of lycopene is greater from heat-processed tomato juice than from unprocessed tomato juice.10 Tomato sauce and ketchup contain 33 to 68 mg of lycopene per 100 g, and raw tomatoes contain 3.1 mg of lycopene per 100 g.4, 6 Mechanical treatment with heat helps release lycopene from the tomato matrix, improving bioavailability, as seen with processed commercial tomato products versus fresh tomatoes. Fat also enhances the absorption of lycopene. Natural sources primarily contain the all-trans form of lycopene; the cis form of lycopene is more bioavailable and is less likely to precipitate and form crystals.11, 12

Uses and Pharmacology

There are numerous studies on the uses of lycopene in treating cancer and cardiovascular disease, as well as on its antioxidant and anti-inflammatory activity.

Antioxidant

In vitro data

Lycopene was 2- to 10-fold more efficient in quenching singlet oxygen than were alpha-tocopherol and beta-carotene.13 The antioxidant activity of lycopene may also be mediated by its bioactive metabolites.14

Clinical data

One study involving 20 patients found a correlation between skin roughness and lycopene dietary concentration.15 In an 8-week, double-blind, randomized, placebo-controlled trial, lycopene supplementation decreased DNA oxidative damage.16 Lycopene may also ameliorate the oxidative stress of cigarette smoke.17, 18

Benign prostatic hypertrophy

A sponsor-funded phase II placebo-controlled randomized clinical trial (n = 57) conducted in men with benign prostatic hypertrophy (BPH) found a commercially available herbal formulation containing pumpkin seed oil, lycopene, saw palmetto, pygeum, and Epilobium parviflorum to significantly reduce median prostate specific scores as well as day time and night time urinary frequency. Improvements were progressive and were observed in several scores at 1 month and in all scores at 3 months.110 The sponsor-funded, double-blind, randomized PROCOMB Italian multicenter trial determined that the combination of saw palmetto, lycopene, selenium (Profluss) plus tamsulosin produced significantly improved prostate symptom scores and Qmax (flow) after 1 year of treatment compared with Profluss or tamsulosin monotherapies in 219 men with BPH/lower urinary tract symptoms.113

Cancer

Human epidemiological evidence indicates that diets high in tomatoes may reduce the risk of cervical, colon, esophageal, rectal, prostate, and stomach cancers.1, 4, 13, 19 Several molecular mechanisms of action4 are proposed for lycopene's anticancer activity, including the following:

  • Antioxidant activity or reduction of free radicals;

  • Antioxidant response element or stimulation of cells to produce enzymes to protect against free radicals;

  • Apoptosis or elimination of unhealthy abnormal cells;

  • Cell-cycle arrest or induction of cell death at the G1 phase;

  • Effect on growth factors and signaling pathways critical for cancer cell growth; and

  • Antimetastatic and anti-invasion activity.

In vitro and animal data

In 1 study, lycopene inhibited human colon carcinoma, myeloid leukemia, and lymphoma cell lines in a dose-dependent manner.3 Lycopene and eicosapentaenoic acid also suppressed signal transduction pathways in human colon cancer cells, thus inhibiting cancer cell growth.20 Another study documented activity against a liver adenocarcinoma cell line and noncancerous lung cell line.2 Lycopene prevented chemically induced DNA and chromosome damage as well as tumor-promoting activity in liver cells through antioxidant activity and inhibition of growth factors and signaling pathways.21, 22, 23

Clinical data

In a clinical trial, lycopene supplementation (30 mg/day for 2 months) had beneficial effects in healthy women with a high risk of breast cancer (n = 36) but not in breast cancer survivors (n = 24).24 In a longitudinal study in which serum levels of various carotenoids and micronutrients were measured in a subset of women from the Women’s Health Initiative clinical trials (N = 5,450), higher baseline levels of lycopene were associated with an increased risk of invasive breast cancer during a median follow-up of 8 years. However, after exclusion of breast cancer cases diagnosed during the first 2 years of follow-up, the association was no longer statistically significant.25 A pooled analysis of 8 prospective studies on carotenoids and breast cancer demonstrated a statistically significant inverse association between carotenoid levels, including lycopene concentrations, and the risk of breast cancer.26

In a large case-control study (N = 4,721) covering 3 years, the risk of pancreatic cancer for men consuming lycopene was reduced 31%. Lycopene protected against cancer by activating cancer-preventive phase 2 enzymes.19, 27

Growing evidence exists for the use of lycopene in prostate cancer prevention. Although numerous animal studies exist,4 only clinical evidence was reviewed in the following studies. In a review of epidemiologic studies, a diet rich in fresh tomatoes, tomato sauce, and pizza reduced the incidence of prostate cancer in a cohort of 40,000 men.19 Increased consumption of tomatoes statistically lowered the risk of prostate cancer in a cohort of 14,000 Seventh-day Adventist men.4, 28 A 2015 systematic review and dose-response meta-analysis of observational studies evaluating dietary intake (n = 13 studies) or blood concentrations (n = 15 studies) of lycopene on the risk of prostate cancer found a reduction in risk by 3% per 1 mg/day increment of dietary intake of lycopene. Elimination of 1 study with wide confidence intervals revealed a significant inverse association between dietary intake as well as blood concentrations of lycopene and prostate cancer risk.116 A meta-analysis of 21 studies provided further evidence of diets rich in tomatoes providing protection against prostate cancer.19 In a Cochrane review of randomized controlled trials of lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer, only 3 of 64 published studies with 154 participants met inclusion criteria. Meta-analysis revealed no difference in prostate-specific antigen levels or in lycopene levels with and without lycopene supplementation. Only 1 study reported incidence of prostate cancer (10% vs 30% in the lycopene vs control groups).29 Another review of 8 randomized controlled trials found study quality varied significantly, making conclusions impossible.30 Lycopene also inhibited the progression of benign prostate hyperplasia.33 Lycopene concentrations changed rapidly in men with prostate cancer given lycopene supplements for several weeks prior to radical prostatectomy. Apoptotic activity was observed and may have been caused by lycopene.34 Prostate volume was reduced in prostate cancer patients taking 30 mg/day of lycopene extract for 3 weeks prior to radical prostatectomy.34 In 997 middle-aged men, an inverse association was found between serum lycopene levels and overall cancer incidence. No association was found between lycopene levels and prostate cancer risk.35 However, a dose-response meta-analysis of 26 studies, 17,517 cases of prostate cancer and 563,299 participants, published through April 2014 identified a linear inverse relationship between lycopene intake and risk of prostate cancer with a dose threshold between 9 and 21 mg/day and an effective plasma concentration found not to exceed 85 mcg/L. For each 5 mg/day increase in lycopene intake, prostate cancer risk decreased with no heterogeneity in studies.115 Oxidative stress is recognized as a major contributor to increased cancer risk. Lycopene's efficient absorption from tomato products facilitates its antioxidant effects and may also play an important role in cancer prevention.36 Lycopene not only achieves high concentrations in the prostate, but also in the testes and adrenal glands. Lycopene intake and decreased cancer risk association has been observed in stomach cancers.37 Lycopene's protective role in the early stages of cervical carcinogenesis was noted in 1 study.38 Plasma levels of lycopene and other carotenoids were lower in women with cervical intraepithelial neoplasia and cervical cancer, suggesting a protective effect of higher lycopene concentrations.39, 40

Lycopene was more efficient than any carotenoid in inhibiting insulin-like growth factor type 1 (ie, high levels of this growth factor are related to an increased risk of cancer) in patients with a higher risk of colorectal cancer.31, 32 A meta-analysis of observational studies explored lycopene consumption and associated risk of colorectal cancer. Of the 15 studies that met inclusion criteria, 11 were case-controlled and 4 were cohort studies with significant heterogeneity found among the studies. Pooled data as well as subgroup analysis (ie, study design, smoking history, alcohol consumption, gender, geographical location) revealed no significant association between consumption of lycopene and the risk of colorectal cancer. Additionally, no dose relationship was observed.118

Cardiovascular disease

The mechanism of action may be associated with antioxidant activity, as well as decreased cell surface adhesion molecule expression and intima-media thickness.

In vitro and animal data

Lycopene suppressed tissue factor activation in vascular thrombosis in human endothelial cells.41 Additional studies found that lycopene reduced expression of cell surface adhesion molecules and binding of monocytes.42, 43 Lycopene also bound and inhibited platelet-derived growth factor, which is associated with the development and progression of cardiovascular disease in rat smooth muscle cells.44 One nutritional study in rabbits compared lycopene's action in reducing the formation of atherosclerotic plaques in the aorta with that of fluvastatin.45 There are studies on the development of more efficient vehicles to deliver lycopene to adipocytes.46

Clinical data

In 19 subjects, lycopene supplementation decreased serum lipid peroxidation and low-density lipoprotein (LDL) oxidation, suggesting a decreased risk for coronary heart disease.47 An epidemiological study in 10 European countries confirmed beneficial effects on the heart correlating with lycopene lipid levels and reduced risk of myocardial infarction.48 The Austrian Stroke Prevention Study found that certain concentrations of lycopene and other antioxidants may protect against cognitive impairment.49 Plasma LDL cholesterol concentrations were reduced by 14% in 6 men consuming dietary supplements of lycopene 60 mg/day for a 3-month period.50 In a 6-week clinical trial, 24 patients receiving fresh tomato and tomato juice twice daily reported reduced triglyceride levels and LDL cholesterol and increased high-density lipoprotein (HDL) cholesterol.51 In studies conducted in overweight individuals, both dietary and supplemental lycopene led to an increase in HDL cholesterol levels52 and a reduction in HDL-associated inflammation.53 In another study, low lycopene concentrations were associated with carotid atherosclerosis in 220 asymptomatic individuals.54

When the effects of tomato extract supplementation were studied in 50 moderately hypertensive individuals, supplementation for 6 weeks was associated with reduced systolic and diastolic blood pressure (SBP and DBP, respectively) and increased serum lycopene levels.55 A meta-analysis of 6 blinded intervention studies (N = 494) evaluating the effects of lycopene or lycopene-containing products on blood pressure found that lycopene supplement decreased SBP significantly (P = 0.012) but not DBP. Doses ranged from 4.5 to 15 mg/day (mean, 12.4 mg/day) for a duration of 4 to 16 weeks (mean, 8.3 weeks); average net change in SBP ranged from −11.5 to 2.4 mm Hg with an overall pooled estimate of −4.95 mm Hg. Reductions were most significant in Asian studies, for those with an initially higher baseline SBP (greater than 120 mm Hg), and with higher dosages (> 12 mg/day).111 Similar results were found from a meta-analysis of 4 intervention trials published between 1955 and 2010.117

The effects of oral lycopene supplementation on vascular function was investigated in a randomized, double-blind, placebo-controlled trial with parallel arms including statin-treated patients with cardiovascular disease (CVD; n = 36) as well as healthy volunteers (n = 36). Participants received lycopene 7 mg or placebo daily for 2 months. Change in forearm blood flow from baseline, as measured by endothelium-dependent vasodilatation (EDV), improved significantly in CVD patients (63% higher; P = 0.008) with values that approximated those of healthy volunteers at baseline. No significant changes in EDV were observed with placebo. Post-hoc analysis demonstrated a positive dose-response correlation between lycopene concentration and absolute change in EDV response between visits (P = 0.019). No significant changes were seen in arterial stiffness or blood pressure between lycopene- and placebo-treated groups. Lycopene was well tolerated; no serious adverse events were reported.114

Cataracts

A meta-analysis of 13 observational studies (n =18,999) evaluated the association between blood levels of antioxidants and vitamins to the risk of age-related cataract. Based on the results of 5 relevant studies with no substantial heterogeneity, lycopene showed no significant association with cataract risk.109

Dental hygiene

Lycopene may be effective as a first-line therapy in treating oral submucous fibrosis56 and in combination with other therapies in treating gingivitis.57 A randomized, double-blind, placebo-controlled trial (n = 50) found no difference between groups treated with lycopene-enriched olive oil or placebo (water) for treatment of burning mouth syndrome or its symptoms.112

Dermatology

Reports of positive outcomes with beta-carotene in skin disorders including cancer, pigment imbalance, and photodermatoses, are available,58, 59, 60, 61 but lycopene may not share these effects because of its structural configuration. One report found beta-carotene to be active in wound healing, while lycopene was inactive.62 Other studies document that lycopene or tomato-derived products rich in lycopene provide photoprotective effects against ultraviolet light-induced erythema.63, 64, 65 Higher levels of lycopene antioxidants in the skin effectively led to lower levels of skin roughness.15 In a placebo-controlled study, lycopene effectively managed oral lichen planus.66

Diabetes

In some animal models, lycopene reduced diabetes-induced learning and memory impairment by decreasing oxidative stress and inflammation.67 Lycopene may also attenuate diabetic neuropathic pain by inhibiting action of tumor necrosis factor (TNF)-alpha and nitric oxide.68 Lycopene may be useful in patients with type 2 diabetes by suppressing oxidative stress and enhancing innate immunity or serum levels of immunoglobulin M.69

Disease prevention

Reports are available in the International Symposia on Lycopene and Tomato Products in Disease Prevention.70, 71 Reviews describing lycopene and disease prevention are also available.72, 73, 74, 75

Inflammation

Epidemiological studies have found that lycopene decreased the inflammation marker C reactive protein.13 The production of inflammatory mediators, such as TNF-alpha, was reduced in patients consuming a tomato-based drink.76 Asthmatic adults receiving lycopene treatment experienced improvement in airway inflammation. Patients treated with the tomato extract also had reduced sputum neutrophil elastase activity.77 In a murine model of asthma, lycopene suppressed infiltration of inflammatory mediators and cells into the lung; decreased airway hyperresponsiveness; and inhibited cell infiltration and invasion.78 Lycopene may also have a role in reducing rhinovirus-induced airway inflammation by potentially inhibiting the formation of reactive oxygen species and decreasing viral replication.79

Dosing

Lycopene administered as a pure compound has been studied in clinical trials at dosages of 8 to 75 mg/day.66, 80, 81, 82, 83, 84 Lycopene is primarily available in capsule and softgel form, with dosage guidelines from manufacturers ranging from 10 to 30 mg taken twice daily with meals. Lycopene is also incorporated in multivitamin and multimineral products.

Lycopene absorption in humans is approximately 10% to 30%, with the remaining excreted.1 The half-life elimination of lycopene in plasma was estimated to be 12 to 33 days, while a single-dose pharmacokinetic study documented 28 to 61 hours.85 The estimated daily dietary intake of the general population is 0.5 to 27 mg per person per day.86 Factors affecting uptake and absorption of carotenoids have been reported.87 Pharmacokinetic parameters of lycopene have been evaluated in humans.39, 88, 89, 90, 91, 92, 93, 94

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Clinical studies evaluating the benefits of supplemental lycopene in pre-eclampsia have produced conflicting results, and some evidence of harm has been reported.95, 96 The amount of lycopene in foods is assumed to be safe. Tomato consumption does increase lycopene concentrations in the breast milk and plasma of lactating women.97

Interactions

Cancer medications

Lycopene reduced cardiotoxicity and renal toxicity during adriamycin administration in rats.98 Lycopene supplementation also partially alleviated bleomycin-induced pulmonary fibrosis in rats by suppressing oxidative stress and inflammatory mediators.99 Lycopene inhibited reactive oxygen species generation in a dose-dependent manner100 and also reduced chromosomal aberrations induced by cisplatin in rats.101 Administering lycopene to rats protected against cardiomyocyte oxidative DNA damage caused by doxorubicin.102, 103

Ciprofloxacin

Lycopene may have an additive effect when used in combination with ciprofloxacin. In rats treated for long-term bacterial prostatitis, bacterial growth and inflammatory changes with the combination of lycopene/ciprofloxacin were reduced, compared with ciprofloxacin or lycopene alone.104

Olestra

Because lycopene requires fat for absorption and transport, studies have documented that patients consuming olestra experienced reduced lycopene absorption. A reduction of nearly 30% over 16 weeks was noted for patients consuming olestra and lycopene. Consumption of lycopene and olestra should be separated by several hours.105

Adverse Reactions

Tomato-based products and lycopene supplements are generally well tolerated. Scientific literature documents some GI complaints, such as diarrhea, dyspepsia, gas, nausea, and vomiting. One trial documented a cancer-related hemorrhage in a patient taking lycopene, but causality was unclear.106 Tomato-based products are acidic and may irritate stomach ulcers.

Toxicology

Avoid use with hypersensitivity to lycopene or to any of its food sources, especially tomatoes.

No toxic effects were observed in rats treated with lycopene 2,000 mg/kg/day for 28 days, an intake similar to approximately lycopene 200 mg/kg of body weight per day in humans.86 Another 13-week toxicity study generated similar results. Some studies documented a protective effect against the oxidative stress of acetaminophen-induced acute hepatotoxicity and against amiodarone-induced lung toxicity.107 Lycopene pretreatment in rats was protective against aflatoxin toxicity by blocking metabolism and metabolic activation of aflatoxin.108

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