Lycopene and the Prevention of Prostate Cancer: The Love Apple Lives up to Its Name

TOP Lycopene and the Prevention... Lycopene and Human Health Processed Tomatoes Are Even... Lycopene Production LITERATURE CITED

Humans cannot synthesize carotenoids de novo and must attain these micronutrients exclusively through their diets. Although the necessity for -carotene as the precursor of vitamin A has been recognized for many years, it is lycopene, a carotenoid that lacks provitamin A activity, that has attracted the most attention of late. Lycopene is the pigment principally responsible for the deep-red color of ripe tomato (Lycopersicon esculentum) fruits and tomato products. Tomato products, including ketchup, tomato juice, and pizza sauce, are the richest sources of lycopene in the U.S. diet, accounting for >80% of the total lycopene intake of Americans (the average American eats 9 kg of fresh tomatoes and 33 kg of processed tomato products each year). The consumption of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases such as cancer and cardiovascular diseases in several recent studies. Many have attributed the health benefits of lycopene to its antioxidant properties (lycopene quenches singlet oxygen almost twice as well as -carotene does), although other mechanisms of lycopene action are possible: The modulation of intercellular communication, hormonal and immune system changes, and alterations of metabolic pathways may also be involved (Rao and Agarwal, 2000).

	Lycopene and Human Health

TOP Lycopene and the Prevention... Lycopene and Human Health Processed Tomatoes Are Even... Lycopene Production LITERATURE CITED

Giovannucci et al. (1995) examined the relationship between the intake of various carotenoids, fruits, and vegetables and the risk of prostate cancer. A dietary questionnaire was sent to almost 50,000 participants in the Health Professional Follow-up Study (HPFS) who were initially free of diagnosed cancer in 1986. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. During this period, 812 new cases of prostate cancer were documented within the study group. Of the 46 vegetables and fruits or related products that were analyzed, only four were significantly associated with lower prostate cancer risk. Of the four, tomato sauce (P < 0.001), tomatoes (P < 0.03), and pizza (P < 0.05), but not strawberries, were primary sources of lycopene. Intakes of the carotenoids -carotene, -carotene, lutein, and -cryptoxanthin were not associated with risk of prostate cancer; only lycopene intake was related to lower risk. These findings suggest that tomato-based foods may be especially beneficial in reducing prostate cancer risk. Of course, other interpretations are possible. For example, perhaps those ethnic groups that traditionally eat more tomato products might be inherently less susceptible to prostate cancer or, alternatively, perhaps those people who eat plenty of tomatoes might also eat plenty of cancer-preventing vegetables in general. More recently, however, Giovannucci et al. (2002) have updated their HPFS study and re-confirmed their earlier results. Moreover, they have found that the associations they uncovered persisted in analyses controlling for fruit and vegetable consumption and for olive oil use (a marker for Mediterranean diet) and were observed separately in men of Southern European or other Caucasian ancestry.

The link between lycopene and the prevention of prostate cancer is also supported by studies that have examined the plasma levels of lycopenes in humans. Lycopene was the only antioxidant that occurred at significantly lower levels in men who went on to develop prostate cancer in comparison with status-matched controls (Gann et al., 1999).

The health benefits of lycopene might extend beyond fighting prostate cancer. Accumulating evidence suggests that the anti-proliferative properties of lycopene may extend to other types of cancer (Giovannucci, 1999). Moreover, lycopene may also be useful in preventing heart disease. Lycopene apparently inhibits cholesterol synthesis and enhances low-density lipoprotein degradation. Available evidence suggests that the thickness of the innermost wall of blood vessels and the risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene (Arab and Steck, 2000).

	Processed Tomatoes Are Even Better

TOP Lycopene and the Prevention... Lycopene and Human Health Processed Tomatoes Are Even... Lycopene Production LITERATURE CITED

It may seem peculiar that tomato paste and other processed tomato products are more effective than fresh tomatoes in preventing prostate cancer. Processed fruits and vegetables have been long considered to have lower nutritional value than their fresh commodities due to the loss of vitamin C during processing. Numerous studies, however, have revealed that tomato processing increases the bioavailability of lycopene to humans (Gartner et al., 1997). Lycopene in fresh tomato fruits occurs almost entirely in the all-trans configuration, but processing converts much of it to cis-forms (Shi and Le Maguer, 2000), and it is these cis-forms that are taken up more readily by humans (Gartner et al., 1997). Indeed, in striking contrast with foods, all-trans lycopene accounts for only 12% to 21% and cis-isomers for 79% to 88% of total lycopene in prostate tissues (Clinton et al., 1996).

	Lycopene Production

TOP Lycopene and the Prevention... Lycopene and Human Health Processed Tomatoes Are Even... Lycopene Production LITERATURE CITED

Due to the spate of recent reports that have suggested an important role for lycopene in human health, consumer demand for lycopene-rich food and nutraceutical products is growing. This increased demand, in turn, has fueled research into identifying alternative lycopene-rich sources and into finding ways to increase lycopene production in tomato fruits. In regard to the first strategy, Fordham et al. (2001) have reported that autumn olive (Elaeagnus umbellata), which has edible fruit, is an extremely rich source of lycopene: Its berries contain lycopene at 15 to 54 mg per 100 g fresh fruit. In contrast, fresh tomato fruit typically has a lycopene content of about 3 mg 100 g¹. This newly identified source of lycopene may provide an alternative to tomato as a dietary source of lycopene.

Our understanding of the physiology underlying lycopene production is still fragmentary. It is known that ethylene, the hormone most associated with ripening, is required for lycopene production in tomato fruits (Theologis et al., 1993). Phytochrome also plays an important role in lycopene production. Brief red-light treatment of harvested mature-green fruit stimulated lycopene accumulation 2.3-fold during fruit development. This red light-induced lycopene accumulation was reversed by subsequent treatment with far-red light, establishing that light-induced accumulation of lycopene in tomato is regulated by fruit-localized phytochromes (Alba et al., 2000). Recently, Mehta et al. (2002) reported that lycopene levels were increased in tomato fruits transgenically engineered to produce higher levels of the polyamines spermine and spermidine during ripening.

Molecular biology has also provided important insights into lycopene biosynthesis. Molecular analyses of yellow-fruited tomato mutants has shown that the lack of carotenoids in the fruits of these mutants is due to the production of aberrant TOM5 transcripts that encode for dysfunctional phytoene synthase (Fray and Grierson, 1993). More recently, Fraser et al. (2002) overexpressed phytoene synthase from the bacterium Erwinia uredovora (crtB) in tomato fruits. Total fruit carotenoids of primary transformants were 2- to 4-fold higher than the controls, and lycopene levels were approximately doubled. Ronen et al. (2000) analyzed two mutations that affect fruit pigmentation in tomato: Beta (B), a single dominant gene that increases -carotene in the fruit, and old-gold (og), a recessive mutation that increases lycopene and lowers -carotene levels. Molecular analyses revealed that B encodes a novel type of lycopene -cyclase, an enzyme that converts lycopene to -carotene, suggesting that -carotene is synthesized de novo during tomato fruit development by the -lycopene cyclase. In wild-type tomatoes, B is expressed at low levels during the breaker stage of ripening, whereas in the Beta mutant its transcription is dramatically increased. Null mutations in the gene B are responsible for the phenotype in og, indicating that og is an allele of B. These results confirm that developmentally regulated transcription is the major mechanism that governs lycopene accumulation in ripening fruits.