Lycopene

Scientific Name(s): psi , psi-carotene

Common Name(s): Lycopene

Uses

The scientific literature documents the antioxidant activity of lycopene and its use in cancer prevention and cardiovascular disease.

Dosing

Lycopene administered as a pure compound has been studied in clinical trials at dosages of 13 to 75 mg/day. Lycopene is mostly 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 during pregnancy and lactation is lacking. 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.

Interactions

Lycopene interacts with some cancer chemotherapy agents, as well as with ciprofloxacin and olestra.

Adverse Reactions

In general, tomato-based products and lycopene supplements are generally well tolerated. The 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, although causality is unclear.

Toxicology

No toxic effects were observed in rats treated with lycopene 2,000 mg/kg/day for 28 days, an intake similar to approximately 200 mg of lycopene per kg of body weight per day in humans. Another 13-week toxicity study generated similar results.

Botany

Lycopene is a common carotenoid compound found in fruits, vegetables, and green plants 1 that is responsible for the red plant pigment found primarily in tomatoes. Other sources include apricot, cranberry, grapes, pink grapefruit, guava, papaya, peaches, and watermelon. 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 considered poisonous and used for decorative purposes only. Columbus may have learned of the nutritional benefits of fruits and tomatoes, until then unknown in the European diet, 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 one 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, as compared with other carotenoids, such as alpha-carotene and beta-carotene. Lycopene is lipophilic and, thus, insoluble in water. Lycopene 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 It is touted as the highest overall single oxygen-quenching carotenoid, double that of beta-carotene. 6

Lycopene is relatively resistant to heat-induced geometrical isomerization in the processing of tomatoes. 7 Processed tomato products are actually a better source of lycopene than fresh tomatoes 8 and are 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 lycopene 33 to 68 mg per 100 g, and raw tomatoes contain lycopene 3.1 mg 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 the crystals affecting solubility. 11 , 12

Uses and Pharmacology

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

Antioxidant
In vitro data

Lycopene was 2- to 10-fold more efficient in quenching singlet oxygen than 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 also may ameliorate the oxidative stress of cigarette smoke. 17 , 18

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 actions 4 are documented 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; Affect growth factors and signaling pathways critical for cancer cell growth; and Antimetastatic and anti-invasion activity.

In vitro and animal data

In one study, lycopene inhibited human colon carcinoma, myeloid leukemia, and lymphoma cell lines in a dose-dependent manner. 3 Lycopene and eicosapentaenoic acid (EPA) 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 and 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 but not in breast cancer survivors. 24

In a large case-control study 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 , 25

Growing evidence exists for the use of lycopene in prostate cancer prevention. Although numerous animal studies exist, 4 only the clinical evidence will be reviewed here. 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 , 26 A meta-analysis of 21 studies provided further evidence of diets rich in tomatoes providing protection against prostate cancer. 19 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. 27 , 28 Lycopene also inhibited the progression of benign prostate hyperplasia. 29 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. 30 Prostate volume was reduced in prostate cancer patients taking 30 mg/day of lycopene extract for 3 weeks prior to radical prostatectomy. 30

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. 31 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. 32 Lycopene's protective role in the early stages of cervical carcinogenesis was noted in 1 study. 33 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. 34

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. 35 Additional studies found that lycopene reduced expression of cell surface adhesion molecules and binding of monocytes. 36 , 37 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. 38 One nutritional study in rabbits compared lycopene's action in reducing the formation of atherosclerotic plaques in the aorta with that of fluvastatin. 39 There are studies on the development of more efficient vehicles to deliver lycopene to adipocytes. 40

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 (CHD). 41 An epidemiological study in 10 European countries, known as the EURAMIC study, confirmed beneficial effects on the heart correlating with lycopene lipid levels and reduced risk of myocardial infarction. 42 The Austrian Stroke Prevention Study found that certain concentrations of lycopene and other antioxidants may protect against cognitive impairment. 43 Plasma LDL cholesterol concentrations were reduced 14% in 6 men consuming dietary supplements of lycopene at 60 mg/day for a 3-month period. 44 Twenty-four patients in a 6-week clinical trial receiving fresh tomato and tomato juice twice daily reported reduced triglyceride levels and LDL cholesterol and increased high-density lipoprotein cholesterol. 45

Other pharmacologic effects
Dental hygiene

Lycopene may be effective as a first-line therapy in treating oral submucous fibrosis 46 and in combination with other therapies in treating gingivitis. 47

Dermatology

Literature addressing beta-carotene's positive outcomes in skin disorders, including cancer, pigment imbalance, and photodermatoses, is available, 48 , 49 , 50 , 51 but lycopene may not share these effects because of its structural configuration. One report finds beta-carotene to be active in wound healing when lycopene was inactive. 52 Other studies document that lycopene or tomato-derived products rich in lycopene provide photoprotective effects against ultraviolet light-induced erythema. 53 , 54 Higher levels of lycopene antioxidants in the skin effectively lead to lower levels of skin roughness. 15

Diabetes

In some animal models, lycopene reduced diabetes-induced learning and memory impairment by reducing oxidative stress and inflammation. 55 Lycopene also may attenuate diabetic neuropathic pain by inhibiting action of tumor necrosis factor-alpha and nitric oxide. 56 Lycopene may be useful in patients with type 2 diabetes by suppressing oxidative stress and enhancing innate immunity or serum levels of immunoglobulin M. 57

Disease prevention

Reports are available on the International Symposium on Lycopene and Tomato Products in Disease Prevention. 58 , 59 Reviews describing lycopene and disease prevention are also available. 60 , 61 , 62 , 63

Inflammation

Some epidemiological studies document that lycopene decreased the inflammation marker C reactive protein. 13 The production of inflammatory mediators, such as tumor necrosis factor-alpha, was reduced in patients consuming a tomato-based drink. 64 Asthmatic adults receiving lycopene treatments experienced improvement in airway inflammation. Patients treated with the tomato extract also had reduced sputum neutrophil elastase activity. 65 In a murine model of asthma, lycopene (a) suppressed infiltration of inflammatory mediators and cells into the lung; (b) decreased airway hyper-responsiveness; and (c) inhibited cell infiltration and invasion. 66 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. 67

Dosage

Lycopene administered as a pure compound has been studied in clinical trials at dosages of 13 to 75 mg/day. 68 , 69 , 70 , 71 , 72 Lycopene is mostly 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. 73 The estimated daily intake of the general population is 0.5 to 27 mg per person per day. 74 Factors affecting uptake and absorption of carotenoids have been reported. 75 Pharmacokinetic parameters of lycopene have been evaluated in humans. 34 , 76 , 77 , 78 , 79 , 80 , 81 , 82

Pregnancy/Lactation

Safety information on the use of lycopene supplements during pregnancy and lactation is lacking. 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. 83

Interactions

Cancer medications

Lycopene helped to prevent cardiotoxicity and renal toxicity during adriamycin administration in rats. 84 Lycopene supplementation also partially alleviated bleomycin-induced pulmonary fibrosis in rats by suppressing oxidative stress and inflammatory mediators. 85 Lycopene inhibited reactive oxygen species generation in a dose-dependent manner 86 and also reduced chromosomal aberrations induced by cisplatin in rats. 87 Administering lycopene to rats protected against cardiomyocyte oxidative DNA damage caused by doxorubicin. 88 , 89

Ciprofloxacin

Lycopene may have an additive effect when used in combination with ciprofloxacin. In rats treated for chronic bacterial prostatitis, bacterial growth and inflammatory changes with the combination of lycopene/ciprofloxacin were reduced, compared with ciprofloxacin or lycopene alone. 90

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. 91

Adverse Reactions

Tomato-based products and lycopene supplements are generally well tolerated. The 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, although causality is unclear. 92

Toxicology

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

No toxic effects were observed in rats treated with lycopene 2,000 mg/kg/day for 28 days, an intake similar to approximately 200 mg lycopene per kg of body weight per day in humans. 74 Another 13-week toxicity study generated similar results. Some studies document a protective effect against the oxidative stress of acetaminophen-induced acute hepatotoxicity and against amiodarone-induced lung toxicity. 93 Lycopene pretreatment in rats helped protect against aflatoxin toxicity by blocking metabolism and metabolic activation of aflatoxin. 94

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