LYCOPENE. A Miracle Nutrient for the 21 Century

By Yousry Naguib, Ph.D.

Supplement Industry Executive, October 2000

Lycopene is a phytochemical nutrient that gives tomatoes (Lycopersicon esculentum) their distinctive red color, and is one of the major carotenoids in the diet of North Americans. Production of tomatoes in the United States ranks second only to potatoes. Lycopene is most abundant in tomatoes (up to 10mg per tomato), and as a consequence, tomatoes and tomato-based foods provide a convenient source of the health benefits of lycopene. Lycopene is also found in few other fruits, such as watermelon, grapefruits and gauva.

Lycopene is one of the main members of the carotenoid family, which includes beta-carotene, the building block for vitamin A. Lycopene has no pro-vitamin A activity. More than 600 naturally occurring carotenoids have been identified, many providing the bright colors of various fruits and vegetables. These compounds are derived from lycopene after steps of cyclization, dehydrogenation and oxidation.

It is their unique chemical structures that contribute to their physiochemical properties and biological activities. They are efficient scavengers of free radicals, particularly singlet oxygen. Other biological functions include enhancement of gap junctions, immunomodultion and regulation of processes involved in carcinogenesis.

About 50 carotenoids can be found in the human diet and about 20 of them have been identified in plasma and tissues. Lycopene and beta-carotene are the most abundant carotenoids in human blood and tissues. Lycopene is found in high concentration in the testes (Table 1) and may, therefore, be useful in preventing prostate cancer.

Since humans can not make carotenoids de novo, we depend upon the diet, exclusively, as the source of these essential nutrients. Tomato products, including ketchup and pizza sauce, are the main sources of lycopene in the American diet, accounting for more than 80% of the total lycopene intake.

Table (1). Carotenoid level in various tissues (microgram per gram wet tissue)

Organ Total carotenoids Lycopene Beta-carotene

Adrenal 18.3 11.56 5.04

Testes 14.3 11.43 2.34

Liver 2.7 1.31 0.98

Pancreas 2.0 0.69 0.67

Ovary 1.4 0.15 0.53

Total carotenoids are the sum of zeaxanthin, cryptoxanthin, lycopene, alpha- and beta-carotene.

Bioavailability

Dietary lycopene is absorbed and distributed in humans and its bioavailability depends on various factors, such as food processing or co-ingestion with fats and fibers. Lycopene in processed tomato products is more bioavailable than that in fresh tomatoes.

Food processing, mechanical homogenization and/or heat treatment may improve lycopene bioavailability, by breaking down tissue cell walls, making lycopene more accessible.

A study conducted by the USDA (United States Department of Agriculture) included fifteen healthy subjects, who ingested lycopene-rich tomato juice, tomato oleoresin, lycopene beadlets (each containing 70-75 mg lycopene) or a placebo for 4 weeks. The results showed that the lycopene levels in buccal mucosa cells (BMC) significantly increased (2-fold) in the cases of oleoresin and beadlets, but was not affected by tomato juice. In a similar study by the USDA with fifteen healthy volunteers, in which lycopene was measured in plasma, the results showed lycopene to be equally bioavailable from tomato juice, oleoresin and beadlets.

A study in Italy on ten healthy women, also found that ingestion of tomato puree (containing 16.5mg total lycopene) resulted in higher plasma lycopene levels than those attained after intake of fresh raw tomato (containing 16.5mg total lycopene), indicating that food matrix affect the absorption of lycopene.

The chemical structure of lycopene also influences its bioavailability, as research has shown the cis-isomers to be more bioavailable than the trans-isomers. Dietary fiber, pectin, guar and alignate were found to markedly reduce lycopene bioavailability in a study with six healthy women.

Antioxidant activity

Oxidative stress is recognized as a major contributor to the increased risk of cancer, coronary heart disease, as well as to a host of other diseases. Recent studies have established a close link between dietary intake of tomatoes and lowered cancer risk.

DiMascio reported that lycopene is the most efficient singlet oxygen quencher among carotenoids, and the quenching ability decreased in the following order: lycopene, gamma-carotene, astaxanthin, canthazanthin, alpha- and beta-carotene, zeaxanthin, lutein and tocopherols.

To assess the role of lycopene intake on lymphocyte DNA resistance to oxidation, five healthy women ate a diet containing tomato puree (providing 16.5mg lycopene per day) and a control group of five women were given a tomato-free diet for three weeks. The plasma lycopene level increased significantly and oxidative damage of lymphocyte DNA decreased only in the group who ate tomato puree. The study concluded that consumption of tomato products may reduce the susceptibility of DNA to oxidative damage and may, therefore, have a preventive role against cancer.

Cardiovascular Diseases

Japanese researchers found that tomato consumption prevents atherosclerosis, by protecting lipids from oxidation, in hyper-cholesterolemic mice fed a diet containing tomato powder. Increases in lipid oxidation, in particular low-density lipoprotein (LDL), are associated with increased risk of coronary heart disease.

A case-controlled study, comprising 108 subjects with aortic atherosclerosis and controls (the Rotterdam Study), revealed an inverse relationship between serum lycopene and the risk of atherosclerosis, suggesting a protective role for lycopene against the development of atherosclerosis.

A study of more than 1,300 European men suggested that consumption of lycopene rich foods reduced the risk of a heart attack by half. A recent study also showed that when healthy human subjects (19) were given lycopene supplementation from tomato juice and spaghetti sauce, their serum lycopene levels were significantly increased, and their LDL oxidation was significantly reduced.

Another study involving 57 patients with well-controlled type 2 diabetes who received tomato juice (500ml/day), vitamin E (800IU/day) and vitamin C (500mg/day) showed a three-fold increase in plasma lycopene levels and a 40 percent decrease in the susceptibility of LDL to oxidation. This study concluded that consumption of tomato juice increases the intrinsic resistance of LDL to oxidation almost as effectively as supplementation with high doses of vitamin E.

These studies clearly demonstrate the relevance of dietary lycopene in protecting LDL from oxidation and hence in reducing the risk of coronary heart disease.

Cancer

Epidemiological Studies

Giovannucci (1999), at Harvard Medical School, reviewing epidemiological literature, found that among 72 studies, 57 reported inverse associations between tomato intake or blood lycopene levels and cancer risk. The evidence was particularly strong for cancers of the prostate, lungs and stomach. Data were also suggestive of benefits of lycopene intake in cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast and cervix.

In Vitro Studies

Lycopene was found to be the most potent carotenoid for inhibiting the proliferation of human aortic smooth muscle cells, and for suppressing the stimulation of mammary cancer cell (MCF7) growth by insulin-like growth factor-I (IGF-I). A high level of IGF-I is considered a risk factor in breast and prostate cancer.

Research has also shown a low dose of lycopene to stimulate gap junction communication between cells, in human skin cells. This communication is lost during malignant transformation of cells. Lycopene is proposed to restore this communication and hence reversing the malignant process.

Colon Cancer

Researchers in Japan reported that rats drinking tomato juice had an appreciable amount of lycopene in their colon mucosa, and had a significantly lower incidence of colon cancer than rats which drank plain water. They suggested that lycopene plays a protective role against colon carcingensis.

Cervix Cancer

A case-controlled study in Japan, involving 156 women with cervical dysplasia and age-matched control women with normal cervical cytology, showed a decreased risk of cervical dysplasia in subjects with the highest serum lycopene levels.

A similar case-control study in the US involving 32 women with incident cervical dysplasia and 113 control women with normal cervical cytology, showed that women in the upper tertile of lycopene intake were one third as likely to have dysplasia as women in the lower tertile. The study indicates lycopene may play a protective role in the early stages of cervical carcinogenesis.

Digestive-tract Cancer

Case-control studies conducted between 1985 and 1991 in northern Italy, where tomato intake is high, showed a consistent pattern of protection at all sites studies (pharynx, esophagus, oral cavity, colon and rectum), most notably for gastrointestinal neoplasms, indicating that tomato intake protects against digestive tract cancers.

A case-control study conducted in Uruguay between 1996 and 1998 and involving 238 cases and 491 controls showed a strong inverse association between the intake of tomato-rich foods and the risk of cancers of the upper aerodigestive tract (oral cavity, pharynx, larynx and esophagus). The study concluded that this protection is due to the joint effect of both lycopene and phytosterols present in tomato-based foods.

Bladder Cancer

An animal study showed that tomato juice exerted an inhibitory effect on the development of transitional cell carcinomas in the urinary bladder of rats. The effect was ascribed to lycopene and other antioxidants in tomato.

Breast Cancer

An Indian epidemiological study found that women with breast cancer had significantly lower serum levels of total carotenoids, including lycopene, and concluded that breast cancer is associated with a low intake of vegetables rich in carotenoids.

A case-controlled study in Uruguay, involving 400 cases and 405 controls, showed that intake of lycopene as well as vegetables, fruits, vitamins C and E, and folate were inversely associated with breast cancer risk.

In a case controlled study, the serum lycopene levels in a cohort of women from the Breast Cancer Serum Bank in Missouri (US), who were followed-up for breast cancer for up to 9.5 years, were inversely associated with the incidence of breast cancer. The study suggested that lycopene and other carotenoids (beta-cryptoxanthin, lutein and zeaxanthin) may protect against breast cancer.

Prostate Cancer

Prostate cancer is the most commonly occurring cancer in US men and the second leading cause of cancer deaths among men in all Western countries. Evidence exists to suggest a role for certain nutrients, such as zinc, selenium, vitamin E, lycopene and phytosterols in protection against prostate cancer.

A five years study, 1986-1992, of the dietary habits of 48,000 male health care professionals found that those eating 10 servings or more a week of cooked tomato products hadprostate cancer risk one third that of those eating less than two servings weekly.

In a nested case-control study researchers at Harvard Medical School obtained plasma samples in 1982 from heathy men enrolled in the Physicians’ Health Study

(clinical trial that randomly assigned more than 22,000 men to take either aspirin and beta-carotene or a placebo). Analysis of the plasma samples of the placebo group for the antioxidants alpha- and beta-carotene, beta-cryptoxanthin, lutein, lycopene, and vitamin E showed lycopene to be the only antioxidant found at significantly lower levels in men who developed prostate cancer within 13 years of follow-up than in matched controls. These data provide further evidence that increased consumption of tomato products and other lycopene containing foods might reduce the occurrence or progression of prostate cancer.

A study, not recorded in the medical database PubMed, conducted at the Karmanos Cancer Institute in Detroit, found that men with early prostate cancer who took lycopene supplements showed signs of decreased malignancr, indicating that lycopene may be useful in treating existing tumors

A synergistic effect of lycopene with other antioxidants such as vitamin E was demonstrated in the strong inhibitory effect of the simultaneous addition of lycopene with vitamin E (at their physiological concentrations; less than 1 microM and 50 microM, respectively) on the prostate carcenoma cell proliferation.

Immune System

A human intervention trial on 23 male non-smokers who were given a diet rich in fruits and vegetables showed that a low carotenoid diet reduced T-lymphocyte functions and addition of tomato juice restored these functions. This immuno-modulation was attributed to active constituents, including lycopene, in tomato juice.

Age-related macular degeneration (ARMD)

Only one study is reported in the literature that claims the health benefits of lycopene in ARMD. This study found that participants in the Beaver Dam Eye Study with the lowest levels of lycopene in their blood were twice as likely to have ARMD, the leading cause of blindness among elderly people.

In summary, studies identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. Lycopene protects against breast, lung and digestive tract cancers; and helps prevent atherosclerosis and slow down aging, and promotes immune function.

REFERENCES

Am J Clin Nutr 1998;68:1187

Am J Clin Nutr 1999;70:490

Br J Nutr 1998;80:353

Arch Biochem Biophys 1989;274:532

Am J Clin Nutr 1999;69:712

Biosci Biotechnol Biochem 1999;63:78

Atherosclerosis 2000;148:49

Mayo Clinic Health Letter, September 1998

Diabetes Care 2000;23:733

J Natl Cancer Inst 1999;91:317

Nutr Cancer 1995;24:257

Arch Biochem Biophys 2000;373:271

Jpn J Cancer Res 1998;89:1003

Br J Cancer 1999;81:1234

Nutr Cancer 1998;31:31

Intl J Cancer 1994;59:181

Oral Oncol 2000;36:47

Jpn J Cancer Res 1998;89:22

J Epidemiol 1999;9:306

Nutr Cancer 1999;35:111

Cancer Causes Control 1998;9:89

J Natl Cancer Inst 1995;87:1767

Cancer Res 1999;59:1225

June 2000 issue of Natural Foods Merchandiser

Biochem Biophys Res Commun 1998;250:582

Br J Nutr 1999;82:383

Arch Ophthalmol 1995;113:1518