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A recently published, National Cancer Institute-sponored study has challenged the idea that lycopene, an antioxidant pigment found in tomatoes and other fruits, can reduce the risk of prostate cancer.

But before anyone jumps to a premature conclusion that this nutrient has little clinical value, it is worth looking more closely at both this new study and at the overall body of clinical data on lycopene. There are many studies indicating that, independent of the prostate cancer question, lycopene has significant health benefits, including cardiovascular risk reduction and even reduction of photodamage caused by UV exposure.

Lycopene is the pigment that gives some fruits their red color. It is found in a variety of produce including watermelon, pink grapefruit and guavas, but tomatoes and foods made from them are by far the most lycopene-rich. Tomatoes and related foods supply about 85% of the lycopene in the US diet (Levy J, Sharoni Y. HerbalGram. 2004; 62: 46–56).

Challenging Data

Lycopene made the news last month when researchers at the Fred Hutchinson Cancer Research Center published a study of over 28,000 men aged 55–74 years, showing no differences in blood lycopene levels between the men who developed prostate cancer over an 8-year period and those who did not.

The men were participants in the ongoing NCI-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial to evaluate cancer screening methods and early cancer markers. They were screened regularly via digital rectal exam and PSA measurement until they developed prostate cancer, died of other causes, or reached the completion of the study period in 2001 (Peters U, et al. Cancer Epidemiol Biomarkers Prev. 2007; 16(5): 962–968).

Lack of a correlation between serum lycopene and presence or absence of prostate cancer led the investigators to conclude that lycopene is not preventive. “It is disappointing, since lycopene might have offered a simple, inexpensive way to lower prostate cancer risk for men concerned about this common disease,” said Ulrike Peters, PhD, MPH, lead author, in a press release immediately following publication. “Unfortunately, this easy answer just does not work.”

Dr. Peters’ findings surprised many advocates of nutrition-based cancer prevention, because they run directly counter to several earlier large studies of lycopene and prostate cancer. Even more surprising was her finding that men with aggressive metastatic prostate cancer had the highest serum beta-carotene levels, a finding that she admitted might be due to chance.

Looking more closely at Dr. Peters’ data, there were 692 new cases of prostate cancer over the 8-year study period, and risk appeared to increase by 14% between the lowest and highest serum lycopene quintiles. However, this trend was not significant (P for trend, 0.28). Interpretation of the PLCO data becomes more difficult when one considers that the baseline median serum lycopene levels in this study were two to six times higher than the medians in other studies reporting serum lycopene levels. The reason for the unusually high baseline levels is unknown.

The researchers did report dietary intake of lycopene, but did not indicate whether the individuals used dietary supplements containing lycopene. Those data would have been useful in interpreting the unusual findings. It is possible that many of the study subjects perceived themselves to be at elevated risk of prostate cancer and took lycopene supplements, hence the higher baseline levels compared with other studies. If this were the case, it would suggest that there is a “ceiling” on the ability of lycopene to reduce risk; beyond a certain level there is no further benefit.

A Broader Context

The PLCO study does have some weight in that it is based on a large population followed for a significant length of time, and it should not be ignored. However, it also must be viewed in the broader scientific context.

Interest in lycopene for prostate health dates back to the mid 1990s, when researchers showed that diets rich in lycopene were associated with reduced prostate cancer risk (Giovannucci E, et al. J Natl Cancer Inst. 2002; 94(5): 391–398. Giovannucci E, et al. J Natl Cancer Inst. 1995; 87(23): 1767–1776. Mohanty NK, et al. Urol Oncol. 2005; 23(6): 383–385). Giovannucci’s large-scale, 12-year study showed a 16% drop in risk in men eating between 3.5 mg (lowest median quintile) and 19 mg (highest median quintile) of lycopene per day. This study, which included over 45,000 men, confirmed earlier ones showing an inverse relationship between lycopene intake and cancer risk.

Men with high-grade prostate intraepithelial neoplasia (HGPIN) are at increased risk of prostate cancer (Mohanty, 2005), and they benefitted from a daily supplement of 8 mg of lycopene from a tomato extract. Over one year, PSA concentrations decreased as serum lycopene levels increased, suggesting that this carotenoid can prevent or delay progression of HGPIN to prostate malignancy.

Chen and colleagues showed that men already have prostate cancer also benefitted from tomato-based foods or supplements. Prostate cancer patients who consumed 30 mg/day of lycopene from tomato-rich foods for three weeks before surgery, had a significant decrease in PSA levels (Chen L, et al. J Natl Cancer Inst. 2001; 93(24): 1872–1879). Analysis of diseased tissue revealed less DNA oxidative damage compared to controls.

Most research has focused on lycopene’s antioxidant capacity. Free radicals and reactive oxygen species are regular by-products of metabolism, and they may react with intracellular molecules and disrupt cell and tissue integrity. Lycopene and beta-carotene, along with vitamins C and E, bind and neutralize these free radicals. Trace elements like zinc, selenium, and copper—also plentiful in tomatoes—augment this effect.

But scavenging free radicals may not be the most important mechanism in reducing cancer risk. Induction of phase II enzymes and modulation of other cellular pathways may be at least as important.

The PLCO data represent a definite challenge to the idea that lycopene can prevent prostate cancer, but they are probably not the final word on this subject. The study does suggest that there may be a healthy upper limit to serum lycopene beyond which there is no additional benefit. The role of lycopene in prostate cancer warrants further investigation.

Not Just a Guy Thing

All this focus on prostate cancer shouldn’t leave you thinking lycopene is just a “guy thing.” Lycopene containing foods have been evaluated in other types of cancer including breast, ovarian, gastrointestinal, lung, and pancreatic malignancies and in pre-cancerous states like cervical intraepithelial neoplasia (VanEenwyk J, et al. Int J Cancer. 1991; 48(1): 34–38) and cervical dysplasia (Kanetsky PA, et al. Nutr Cancer. 1998; 31(1): 31–40).

Serum lycopene correlates inversely with breast cancer risk. Women in the highest lycopene quartile were at half the risk compared to those in the lowest quartile (Dorgan JF, et al. Cancer Causes Control. 1998; 9(1): 89–97). Similar results were found by Levi in a study in which disease risk was decreased 57% between the lowest (1.5 mg) and the highest (6 mg) daily lycopene intake (Levi F, et al. Int J Cancer. 2001; 91(2): 260–263). A similar pattern was shown for ovarian cancer (Cramer DW, et al. Int J Cancer. 2001; 94(1): 128–134). At the lowest daily intake (5 mg), risk was increased by 63% compared to the highest highest (>15 mg) daily intake.

For GI cancer, subjects who ate seven servings of tomatoes a week had a significantly lower risk than those who ate fewer (Franceschi S, et al. Int J Cancer. 1994; 59(2): 181–184).

Men and women getting 18 mg and 14.6 mg of lycopene per day, respectively, had a decreased risk of lung cancer when compared to the lowest intakes (3.7 mg and 4.4 mg, respectively). Of the 786 subjects who developed lung cancer, 11% (84) never smoked, 44% (345) were past smokers, and 45% (345) were current smokers (Michaud DS, et al. Am J Clin Nutr. 2000; 72(4): 990–997). It seems lycopene is protective against lung cancer, especially in current smokers.

Lycopene may reduce pancreatic cancer risk as well, and this appears to be a gender-specific effect. In a case-controlled study, men, but not women, who consumed about 7 mg daily of lycopene from foods had a 31% risk reduction compared to those who ate only about 0.9 mg a day. The women had a small risk reduction (9%), but it was not significant (Nkondjock A, et al. J Nutr. 2005; 135(3): 592–597).

As was the case in men with PIN, women with cervical intraepithelial neoplasia (CIN) also benefit from a lycopene-rich diet (VanEenwyk, 1991; Kanetsky, 1998). The risk of cervical dysplasia was reduced by one-third in those getting 1 mg per day of lycopene from foods compared to those getting only about 0.4 mg a day. These are small intakes, and perhaps consuming larger amounts may yield even greater benefit.

Tomatoes and tomato-based foods appear to reduce cancer risk; and even eating as few as one tomato a day may be enough to cut GI cancer risk; more (2–3 servings of tomatoes daily) may reduce the risk of other cancers.

To reduce lung cancer risk, especially in smokers, requires about 15–18 mg per day of tomato lycopene. That’s equivalent to drinking one glass of tomato juice or one having plate of pasta with tomato sauce each day. Using tomato-based foods or supplements of lycopene from tomato extract provide more lycopene per serving, and for many people, may be easier to consume than fresh tomatoes.

The Heart of the ‘mato

There are also a number of studies showing that increased lycopene intake can markedly reduce risk of myocardial infarction, stroke, acute coronary events, and platelet activation.

It is also a natural antihypertensive. A tomato extract oleoresin containing 15 mg lycopene significantly lowered BP in patients with grade-1 hypertension (Engelhard, 2006) Adipose lycopene content, which reflects long-term daily intake, is inversely related to risk of acute MI (Kohlmeier L, et al. Am J Epidemiol. 1997; 146(8): 618–626). The odds ratio for MI was 0.52 for the highest versus lowest adipose lycopene levels.

The CV benefit of lycopene may be age-related, and it seems to favor younger versus older people. In one study of older men (average age 70 years), there was no decrease in CVD risk between the lowest (46 mcg/L; 0.08 μmol/L) and the highest lycopene quartiles (153 mcg/L; 0.27 μmol/L) (Sesso HD, et al. Am J Clin Nutr. 2005; 81(5): 990–997). But an earlier study showed an inverse relationship between serum lycopene and CVD in younger males (Rissanen, 2001). Subjects in the lowest quartile had a 3.3-fold increase in risk of coronary events or stroke compared with those in the highest quartile.

Lycopene reduces platelet activation, and this may be an important aspect of its cardioprotective effect, given that activated platelets correlate with thrombotic events. O’Kennedy and colleagues showed that at two different doses, a lycopene-rich tomato extract could reduce platelet activation by 8–21%, depending on the type of platelet-stimulating agent used (O’Kennedy N, et al. Am J Clin Nutr. 2006; 84(3): 561–569).

In aggregate, the data suggest that eating as few as two tomatoes a day (about 6–16 mg of lycopene) or taking a supplement containing 15 mg of lycopene from a tomato extract is enough to significantly reduce CV risk through several different mechanisms.

Red Prevents Red

For many people, summer means sunburn. Fortunately, tomatoes may even be good for preventing that, too!

Tomato-based foods and a tomato oleoresin extract were both effective at reducing the degree of redness after a controlled exposure to UV radiation. Daily consumption of tomato paste containing 16 mg of lycopene resulted in a 40% lesser burn compared to placebo under controlled conditions (Stahl W, et al. J Nutr. 2001; 131: 1449–1451). A follow-up study using the same sunburn model showed that 10 mg of lycopene in either the synthetic or natural form, minimized redness post-burn; however, the natural sources were more effective.

The debate over synthetic versus natural lycopene supplements has gone on for some time. Both can increase serum lycopene levels if consumed regularly for extended periods of time. But the natural form has a major advantage in that it provides other beneficial bioactive compounds like phytofluene and phytoene (Aust O, et al. Int J Vitam Nutr Res. 2005; 75(1): 54–60), which may be important not only to offset the effects of the sun, but also to help reduce the risk of diseases such as CVD and cancer.

While it won’t likely replace a good sunscreen, daily consumption of about 10–16 mg of lycopene from food or a natural extract can reduce the redness and photodamage associated with sunburn.

In most studies, high intakes of tomatoes, tomato-based foods, or a natural tomato extract provided significant benefits in terms of reducing disease risk or improving management of various conditions.

Lycopene content in tomatoes varies by strain, agricultural conditions, and ripeness. As a rough estimate, the average tomato contains 5–10 mg of lycopene, along with a lot of other nutrients, like alpha-tocopherol, beta-carotene, phytoene, and phytofluene (Engelhard YN, et al. Am Heart J. 2006; 151(1): 100.e1–100.e6). Lycopene may be a more potent antioxidant than alpha- or beta-carotene (Rissanen TH, et al. Br J Nutr. 2001; 85(6): 749–754. Chen L, et al. J Natl Cancer Inst. 2001; 93(24): 1872–1879).

Interestingly, bioavailability of lycopene increases with cooking, though from a practical viewpoint, differences are pretty small. Paetau and colleagues measured the bioavailability of lycopene from tomatoes, tomato-containing products like tomato juice, or tomato extract supplements. Mean increases in plasma lycopene were similar after ingestion of 70–75 mg of lycopene from tomato juice, and two dietary supplements containing a natural lycopene extract (Paetau I, et al. Am J Clin Nutr. 1998; 68(6): 1187–1195). For optimal bioavailability, the tomatoes and tomato-based foods should be eaten with a little bit of a healthy oil.

One need not gorge oneself on tomatoes to get the health benefits of lycopene. Remember that in most positive studies, the daily lycopene intake was modest, in the range of 2 mg to 15 mg.

This amount can easily be achieved by having a tomato-based product or a couple of fresh tomatoes each day. Ketchup is one of the densest sources of lycopene, and has the added advantage of being liked by nearly everyone, even avowed vegetable-haters. Using ketchup and tomato pastes regularly will easily provide beneficial amounts of lycopene and other bioactive compounds. Natural tomato extract oleoresin in dietary supplement form is equally effective.

Stacey J. Bell, D.Sc, RD, is a research scientist at IdeaSphere, Inc, Grand Rapids, MI. She can be reached at: sbell@isibrands.com. The following individuals also contributed to this article: Wendy Van Ausdale, Research Associate, IdeaSphere; Greg Grochoski, Director, Research & Development, IdeaSphere; Dr. Yoav Sharoni and Dr. Joseph Levy, both Professors of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel. IdeaSphere is a manufacturer of dietary supplements, including products that contain lycopene. Drs. Levy and Sharoni are paid consultants to Lycored Natural Products, a manufacturer of commercially available lycopene from tomatoes.