lycopene

DietaryLycopene: Its

Properties andAnticarcinogenic

EffectsPreeti Singh and G.K. Goyal

ABSTRACT: Lycopene is the principal pigment of the carotenoids naturally found in tomatoes and is important notonly because of the color it imparts but also because of the recognized health benefits associated with its presence.Red tomatoes typically contain about 95% of their lycopene as the all-trans isomer, the most stable form. In tangerinetomatoes, on the other hand, the lycopene is present as tetra-cis-lycopene, a geometric isomer of all-trans lycopene.Lycopene is a major component found in blood serum. This carotenoid has been extensively studied for its antioxidantand cancer-preventing properties. Prevention of heart disease has been shown to be another antioxidant role playedby lycopene because it reduces the accumulation of platelets that eventually lead to blood clots, heart attacks, andstrokes. In contrast to many other food phytonutrients whose effects have only been studied in animals, lycopenefrom tomatoes has been repeatedly studied in humans and found to be protective against several cancers, which nowinclude colorectal, prostate, breast, lung, and pancreatic cancers. This review outlines the background informationdealing with lycopene and presents the most comprehensive and current understanding of its potential functionalrole in human health.

IntroductionChronic diseases, including cancer and cardiovascular dis-

eases, are the main causes of death in the Western world. Alongwith genetic factors and age, lifestyle and diet are also consid-ered to be the important risk factors (Trichopoulos and Willett1996). About 50% of all cancers have been attributed to diet(Williams and others 1999). Oxidative stress induced by reactiveoxygen species is one of the main foci of recent research relatedto cancer and cardiovascular diseases (Rao and others 2003). Re-active oxygen species are highly reactive oxidant molecules thatare generated endogenously through regular metabolic activity,lifestyle activity, and diet. They react with cellular components,causing oxidative damage to such critical cellular biomoleculesas lipids, proteins, and DNA (Halliwell 1994; Witztum 1994;Ames and others 1995; Pincemail 1995). There is strong evidencethat this damage may play a significant role in the causationof several chronic diseases. Antioxidants are protective agentsthat inactivate reactive oxygen species, and, therefore, signifi-cantly delay or prevent oxidative damage. Antioxidants such assuperoxide dismutase, catalase, and glutathione peroxidase arenaturally present within human cells. In addition, antioxidantssuch as vitamin E, vitamin C, polyphenols, and carotenoids areavailable from food. Current dietary guidelines to combat chronic

MS 20070844 Submitted 11/15/2007, Accepted 3/4/2008. Authors are withFood Packaging Lab, Dairy Technology Div., Natl. Dairy Research Inst.,Karnal 132 001, Haryana, India. Direct inquiries to author Singh (E-mail:preeti [email protected]).

diseases, including cancer and coronary artery disease, recom-mend increased intake of plant foods, including fruits and veg-etables, which are rich sources of antioxidants (USDA/USHHS2000). The role of dietary antioxidants, including vitamin C, vi-tamin E, carotenoids, and polyphenols, in disease prevention hasreceived much attention in recent years (Halliwell and others1995; Sies and Stahl 1995; Campbell and others 2004; Rebouland others 2005; Kun and others 2006; Ignarro and others 2007).These antioxidants appear to have a wide range of anticancerand antiatherogenic properties (Ziegler 1991; Block 1992; Rimmand others 1993; Halliwell and others 1995; Sies and Stahl 1995;Kritchevsky and others 1998) and age-related macular degener-ation (AMD) (Beatty and others 1999). These observations mayexplain the epidemiological data indicating that diets rich in fruitsand vegetables are associated with a reduced risk of numerouschronic diseases (Block and others 1992; Steinmetz and Potter1996). Another dietary antioxidant thought to be important in thedefense against oxidation is lycopene, of which tomatoes are animportant dietary source (Clinton 1998; Rao and Agarwal 1999).

Lycopene is a bioactive carotenoid present in many fruits andvegetables. Lycopene, similar to other carotenoids, is a naturalfat-soluble pigment found in certain plants and microorganisms,where it serves as an accessory light-gathering pigment and toprotect these organisms against the toxic effects of oxygen andlight. Lycopene is one of more than 600 carotenoids found in na-ture, and Willstatter and Escher (1910) first reported its isolationprocedures. Carotenoids can be characterized as hydrocarboncarotenoids such as lycopene and β-carotene or oxycarotenoids,which are xanthophylls such as lutein (Isler 1973). The relevance

C© 2008 Institute of Food Technologists Vol. 7, 2008—COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY 255

CRFSFS: Comprehensive Reviews in Food Science and Food Safety

of carotenoids to human nutrition and health has historicallybeen confined to those possessing pro-vitamin A activity suchas α-carotene and β-carotene. However, other carotenoids havealso emerged as important dietary phytochemicals. Among thesecarotenoids having potentially beneficial biological activitiesother than a role as vitamin A precursor, lycopene, in particular, isthe one with the most promising implications for human health.Of the more than 50 dietary carotenoids, lycopene, found primar-ily in tomatoes and tomato products, is the most prevalent in theWestern diet and the most abundant in human serum. It was firstisolated by Hartsen (1873) from Tamus communis L. berries asa deep red color crystalline pigment. Millardet (1875) obtaineda crude mixture containing lycopene from tomatoes, referring toit as solanorubin. Duggar (1913) referred to lycopene as lycop-ersicon in his work detailing the effects of growth conditions onits development. Schunck (1903) gave lycopene its name aftershowing that this pigment from tomato had a different absorptionspectrum than carotenes from carrots. It is the main carotenoidresponsible for the red color of tomato products and has beensuggested as the main phytochemical responsible for the ben-eficial effects of tomatoes. As data for the lycopene content offoods have become available in recent years, accumulating ev-idence has shown an inverse correlation between consumptionof tomato products rich in lycopene and the risk of several typesof cancer and cardiovascular diseases.

Lycopene: Structure and PropertiesLycopene is a natural pigment synthesized by plants and mi-

croorganisms but not by animals. It is a carotenoid, an acyclic iso-mer of ß-carotene. Lycopene is a highly unsaturated hydrocarboncontaining 11 conjugated and 2 unconjugated double bonds. Asa polyene it undergoes cis-trans isomerization induced by light,thermal energy, and chemical reactions (Zechmeister and others1941; Nguyen and Schwartz 1999). The color of lycopene is dueto its many conjugated carbon double bonds. Each double bondreduces the energy required for electrons to transition to higherenergy states, allowing the molecule to absorb visible light ofprogressively longer wavelengths. Lycopene absorbs most of thevisible spectrum, so it appears red. If lycopene is oxidized (forexample, by reacting with bleaches or acids), the double bondsbetween carbon atoms will be broken, cleaving the moleculeinto smaller molecules each double-bonded to an oxygen atom.Although C=O bonds are also chromophoric, the much shortermolecules are unable to absorb enough light to appear colorful.A similar effect occurs if lycopene is reduced; reduction may sat-urate (convert the double bonds to single bonds) the lycopenemolecule, diminishing its ability to absorb light.

In the common variety of tomatoes, Lycopersicon esculentum,lycopene is found predominantly in the all-trans configuration,the most thermodynamically stable form (Zechmeister and others1941), and at concentrations of 3.1 to 7.7 mg/100 g of ripe fruit.In human plasma, lycopene is present as an isomeric mixture,with 60% of the total lycopene as cis isomers. The molecular for-

Figure 1 --- All-translycopene.

mula of lycopene (C40H56) was first determined when Willstatterand Escher (1910) presented their study showing that lycopeneis an isomer of the carotenes. Karrer and others (1928, 1930)published the chemical structure of lycopene, which was subse-quently confirmed by Kuhn and Grundmann (1932) by identify-ing its degradation products following chromic acid oxidation.The molecular weight of lycopene is 536.85 Da, with the gen-eral structure being an aliphatic hydrocarbon with 11 conjugatedcarbon–carbon double bonds (Figure 1), which imparts a red col-oration as well as fat- and lipid-soluble characteristics. Lycopeneabsorbs light in the visible range, and a petroleum ether solutionof lycopene has maximum absorption λmax at 472 nm and a differ-ential emission wavelength of 3078 (Davies 1976; Moss and Wee-don 1976). As a result of the 11 conjugated carbon–carbon doublebonds in its backbone, lycopene can theoretically assume 211 or2048 geometrical configurations (Zechmeister and others 1943;Chasse and others 2001). All-trans, 5-cis, 9-cis, 13-cis, and 15-cis are the most commonly identified isomeric forms of lycopene(Figure 2), with the stability sequence being 5-cis > all-trans >9-cis > 13-cis > 15-cis > 7-cis > 11-cis, so that the 5-cis form isthermodynamically more stable than the all-trans-isomer (Chasseand others 2001).

Dietary Lycopene: Food Sources and BioavailabilityThe human body is unable to synthesize carotenoids, which

qualifies diet as the only source of these components in bloodand tissues. At least 85% of our dietary lycopene comes fromtomato fruit and tomato-based products (Bohm and others 2001).Red fruits and vegetables, including tomatoes, watermelons, pinkgrapefruits, apricots, and pink guavas, contain lycopene (Nguyenand Schwartz 1999). Tomatoes are an integral part of the humandiet and are commonly consumed in fresh or in processed formsuch as tomato juice, ketchup, paste, sauce, and soup. Lycopeneis found predominantly in the chromoplast of plant tissues. Intomatoes, lycopene biosynthesis increases dramatically duringthe ripening process as chloroplasts undergo transformation tochromoplasts (Kirk and Tilney-Basset 1978). Laval-Martin (1974)categorized tomato chromoplasts into 2 types: globulous chromo-plasts containing mainly β-carotene, while chromoplasts in theouter part of the pericarp contain voluminous sheets of lycopene.The development and ultrastructure of these sheets of lycopenewere studied by Benshaul and Naftali (1969), who named themcrystalloids. Mohr (1979) noted that in both normal red and high-lycopene varieties of tomatoes, the development of the pigmentbodies is similar, following the same sequence of granal mem-brane loss, globule size and density increase, and deposition ofcrystal bodies along the extended thylakoid system.

Raw and processed tomatoes are the main sources of lycopenein the human diet. However, the lycopene content of tomatoproducts is highly variable, being affected by factors such as va-riety (Hart and Scott 1995; Abushita and others 2000), ripeness(Fraser and others 1994), climate and geographical site of pro-duction (Scalfi and others 2000), and processing (Tonucci and

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Dietary lycopene: anticarcinogenic effects

Figure 2 --- Lycopene geometrical isomers.

Table 1 --- Common food sources of dietary lycopene.

AmountAmount per serving

(mg/100 gFood source Type wet weight) mg Serving size

Apricots Fresh 0.005 0.007 140 gApricots Canned, drained 0.065 0.091 140 gApricots Dried 0.86 0.34 40 gChilli Processed 1.08 to 2.62 1.40 to 3.41 130 gGrapefruit Pink, fresh 3.36 4.70 140 gGuava Pink, fresh 5.40 7.56 140 gGuava juice Pink, processed 3.34 8.35 240 mL (250 g)Ketchup Processed 16.60 3.32 1 tbsp (20 g)Papaya Red, fresh 2.00 to 5.30 2.8 to 7.42 140 gPizza sauce Canned 12.71 15.89 125 gPizza sauce From pizza 32.89 9.867 125 gSalsa Processed 9.28 3.71 2 tbsp (40 g)Spaghetti sauce Processed 17.50 21.88 125 gTomatoes Red, fresh 3.1 to 7.74 4.03 to 10.06 130 gTomatoes Whole, peeled, processed 11.21 14.01 125 gTomato Juice Processed 7.83 19.58 240 mL (250 g)Tomato soup Canned, condensed 3.99 9.77 245 gTomato paste Canned 30.07 9.02 30 gWatermelon Red, fresh 4.10 11.48 280 gVegetable juice Processed 7.28 17.47 240 mL (250 g)

others 1995; Shi and Le Maguer 2000; Re and others 2002). Forexample, although the median lycopene content of raw toma-toes has been given as 3100 µg/100 g, it has also been reportedto vary between 879 and 4200 µg/100 g wet weight (Mangelsand others 1993). The range may be even larger in processedtomato products where different preparation procedures add tothe variability in the resulting lycopene content. In certain vari-eties, such as Lycopersicon pimpinellifolium, levels as high as 40mg/100 g of tissue have been reported, accounting for 95% to100% of the total carotenoids content of these tomatoes (Porterand Lincoln 1950). Recent advances in isolation and chromato-graphic separation methodologies have shown that lycopene ismuch more widely distributed in nature than once thought. Ta-ble 1 (Nguyen and Schwartz 1999) lists various food sources ofdietary lycopene, taking serving sizes into consideration.

The matrix in which lycopene is found in foods appears tobe an important determinant of its biological value (Castenmillerand others 1999), and release of lycopene from this matrix is the1st step in the absorptive process (Williams and others 1998). Theprocess of cooking usually makes lycopene more bioavailable byits release from the matrix into the lipid phase of the meal. Foodprocessing also has been shown to increase the biological value.

The problem of wide variability in lycopene content of foodswill also contribute to the wide variation in population estimatesof lycopene intake in other studies (Johnson-Down and others2002). Tomato paste (Gartner and others 1997) and tomato puree(Porrini and others 1998) have been shown to be more bioavail-able sources of lycopene than are uncooked food sources suchas a raw tomato. The uptake of lycopene into intestinal mucosalcells is aided by the formation of bile acid micelles. Becausebile production is stimulated by dietary fat, consuming fat with alycopene-containing meal increases the efficiency of absorption(Stahl and Sies 1992). Data from human studies in India havesuggested that a minimum of 5 to 10 g of fat in a meal is requiredfor the absorption of carotenoids (Reddy 1995). Conversely, anumber of other investigators have found that the carotenoidsare absorbed from lower-fat meals. Factors such as certain fibers

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(Erdman and others 1986; Rock and Swendseid 1992; Demingand others 2000), fat substitutes (Weststarte and van het Hof1995), plant sterols (Weststarte and Meifer 1995), and cholesterollowering drugs (Elinder and others 1995) that interfere with theincorporation of lycopene into micelles can potentially decreasethe efficiency by which this carotenoid is absorbed. Certain fatsubstitutes may also create a hydrophobic sink in the lumen ofthe small intestine, binding lycopene and thereby making it un-available for uptake. The uptake of lycopene by the brush bordermembrane of the intestinal mucosal cell is thought to be by pas-sive diffusion, and little is known about the intramucosal process-ing of lycopene. It remains to be elucidated whether lycopene istransported intracellularly by specific proteins or whether it mi-grates in lipid droplets (Gugget and Erdman 1996). Within theenterocyte, β-carotene and other pro-vitamin A carotenoids suchas α-carotene and β-cryptoxanthin can be metabolized to vita-min A or retinol by a specific enzyme, β-carotene-15,15′ dioxy-genase (Olson 1961; Olson 1989). Unlike β-carotene, lycopeneis not metabolized to pro-vitamin A carotenoids but oxidativemetabolites of lycopene have been found in human serum, al-though little is known about the sites and mechanisms involvedin their formation (Khachik and others 1997). Digestive processeswill certainly influence lycopene bioavailability. Several factorsaffect initial carotenoid release from the physical food matrix andtransfer and distribution into lipid droplets within stomach andproximal duodenum. Perhaps of major importance, dietary lipidsmay serve a critical role in dissolution and subsequent absorp-tion of a very hydrophobic carotenoid such as lycopene. Pan-creatic lipases and bile salts act upon the carotenoid-containinglipid droplets entering the duodenum and form multilamellar lipidvesicles containing the carotenoid. The transfer of lycopene, likeother carotenoids, from the micelle into the mucosal cells ap-pears to occur via passive diffusion. Factors such as the struc-tural features of the carotenoid, the dietary fat content, fatty acidpatterns, fiber, and others food components may influence thecarotenoid content of micelles and subsequent mucosal transfer(Parker 1996).

Lycopene exits the mucosal cell in chylomicrons, which are se-creted via the mesenteric lymph system into the blood. Throughthe action of lipoprotein lipase in chylomicrons, lycopene andother carotenoids have the potential to be taken up passivelyby various tissues, including adrenals, kidney, adipose, spleen,lung, and reproductive organs, before clearance of chylomicronremnants by the liver via the chylomicron receptor. Carotenoidscan accumulate in the liver or can be repackaged into very-low-density lipoprotein (VLDL) and sent back into the blood. Uptakeof carotenoids into tissues from VLDL and LDL is thought to occurvia the LDL receptor, and the tissues with the highest concentra-tions of carotenoids (liver, adrenal, testes) tend to have high LDLreceptor activity. Lycopene is a predominant carotenoid in the hu-man liver, adrenals, adipose tissue, testes, and prostate (Kaplanand others 1990; Stahl and others 1992; Clinton and others 1996;Clinton 1998; Freeman and others 2000). In a recent study con-ducted by Rao and others (1998), the average daily dietary intakeof lycopene, assessed by means of a food-frequency question-naire, was estimated to be 25 mg/d with processed tomato prod-ucts, accounting for 50% of the total daily intake. Although com-parative bioavailability values for lycopene from different tomatoproducts are unknown, lycopene from processed tomato prod-ucts appears to be more bioavailable than that from raw toma-toes (Table 1) (Stahl and Sies 1992; Gartner and others 1997;Porrini and others 1998; Bohm and Bitsch 1999; van het Hof andothers 2000). The release of lycopene from the food matrix dueto processing, the presence of dietary lipids, and heat-inducedisomerization from all-trans to a cis conformation enhances ly-copene bioavailability (Rao and Agarwal 1999). Lycopene from

heat-induced cis-isomer-rich tomato sauce is more bioavailablethan from all-trans-rich tomato sauce in human subjects (Unluand others 2007a). The bioavailability of lycopene is also af-fected by dosage and the presence of other carotenoids, such as β-carotene. Johnson and others (1997) found that the bioavailabilityof lycopene was significantly higher when it was ingested alongwith β-carotene than when ingested alone. Erdman (2005) stud-ied the effect of nutritional and hormonal status on the bioavail-ability, uptake, and distribution of different isomers of lycopenein F344 male rats and concluded that cis-isomer forms of ly-copene are more bioavailable than is all-trans-lycopene, and ly-copene accumulation in some tissues is inversely related to an-drogen status and appears to be inversely related to energy intake;also, tomato carotenoids differentially distribute in tissues of F344rats. Their results clearly demonstrate that all tomato carotenoidscannot be assumed to be absorbed and metabolized the same.Moreover, their absorption and metabolism are affected by hor-monal status of the host and perhaps the overall redox state of thetissue.

Red tomatoes typically contain 94% to 96% all-trans-lycopene,which is the thermodynamically most stable form (Porrini andothers 1998). In contrast, human plasma and tissues containat least 50% cis-isomers, the most common isomeric lycopeneforms being all-trans-, 5-cis-, 9-cis-, 13-cis-, and 15-cis-lycopene.Contrarily, in tangerine variety tomatoes, the predominant ly-copene isomer present is prolycopene (tetra-cis-lycopene), a ge-ometric isomer of all-trans-lycopene, giving this fruit a character-istic orange color. Carotenoid isomerase is the enzyme in toma-toes responsible for the conversion of poly-cis-lycopene to all-trans-lycopene. Tangerine tomatoes lack this enzyme and there-fore accumulate tetra-cis-lycopene with four (7Z , 9Z , 7′Z , 9′Z -tetra-cis) of its 11 double bonds in the cis-configuration (Isaac-son and others 2002). Unlu and others (2007b) studied thecarotenoid absorption in humans from the tomato sauces pro-duced from tangerine tomatoes, high in cis-lycopene, especiallyprolycopene (7 Z , 9Z , 7′ Z , 9′ Z ) and high-β-carotene toma-toes, as an alternative dietary source of β-carotene. The servingsize was 150 g (containing 15 g of corn oil), tangerine saucecontaining 13 mg of lycopene (97.0% as cis-isomers) and high-β-carotene sauce containing 17 mg of total β-carotene (1.6% asthe 9-cis-isomer) and 4 mg of lycopene. Carotenoids were deter-mined in the plasma triacylglycerol-rich lipoprotein fraction byHPLC-electrochemical detection. Baseline-corrected areas un-der the concentration compared with time curves (AUC) wereused as a measure of absorption. AUC0–9.5h values for total ly-copene in the tangerine sauce group were 870 ± 187 (nmol.h)/Lwith > 99% as cis-isomers (59% as the tetra-cis-isomer). TheAUC0–9.5h values for total β-carotene and lycopene after con-sumption of the high-β-carotene sauce were 304 ± 54 (4% as9-cis-carotene) and 118 ± 24 (nmol.h)/L, respectively. Lycopenedose-adjusted triacylglycerol-rich lipoprotein AUC responses inthe tangerine sauce group were relatively high when comparedto the high-β-carotene group. The results support the hypothesisthat lycopene cis-isomers are highly bioavailable and suggest thatspecial tomato varieties can be utilized to increase both the in-take and bioavailability of health-beneficial carotenoids. In theirstudy, the percentage of tetra-cis-lycopene of total lycopene de-creased after processing, while that of all-trans-lycopene stayedabout the same and the sum of other cis-lycopene isomers in-creased. According to Allen (2000), all-trans-lycopene is the morethermodynamically stable compound. Co-consumption of lipidsalso has been shown to be important (Brown and others 2004;Unlu and others 2005). In addition to an increase in carotenoidsolubility during digestion, it was postulated that carotenoidsare kept in the enterocyte and are not released until long-chainfatty acids (12:0 to 18:0) from a present or subsequent meal



enable carotenoid packaging into chylomicrons (Borel and others1998).

Lycopene absorption from the tangerine variety compared withthe high-β-carotene variety was about 2.5 times higher, evenwhen adjusted for lycopene doses. The lower dose given withinthe high-β-carotene variety could have been expected to result ina rather higher fractional absorption, as lower lycopene doses areassumed to be better absorbed compared to large doses (Gustinand others 2004). Thus, high lycopene bioavailability when in-gested predominantly in the form of cis-isomers (Unlu and oth-ers 2007b). In a recent human study by Allen (2000), lycopeneplasma responses were studied in a human crossover study fol-lowing the consumption of 140 g/d of cis-lycopene-rich tangerineor all-trans-lycopene rich roma sauces for 4 d. Even though thetotal amount of lycopene consumed in the tangerine group waslower, a 20% compared with 2% increase in plasma lycopeneconcentration after tangerine and roma sauce consumption wasobserved, respectively, suggesting that cis-lycopene was moreefficiently absorbed than the all-trans-isomer. Similarly, prelimi-nary results by Ishida and others (2005) reported higher plasma ly-copene responses following tangerine compared with red tomatosauce consumption.

Enzymatic and Oxidative Metabolites of LycopeneLycopene has been implicated as a potential chemopreven-

tive agent with respect to cancer. Reports from the epidemiolog-ical studies (Helzlsouer and others 1989; Franceschi and others1994; Giovannucci and others 1995; Zhang and others 1997;Gann and others 1999), studies in animals (Nagasawa and oth-ers 1997; Narisawa and others 1998; Okajima and others 1998)and cell cultures (Bertram and others 1991; Zhang and others1992; Kim 1995; Levy and others 1995; Tsushima and others1995) all suggest that lycopene has anticarcinogenic properties.These reports have given rise to several hypotheses that the in-verse relation between lycopene intake and cancer risk might beascribed to (1) lycopene as an antioxidant, (2) increasing cell–cell communication, (3) reducing mutagenesis, (4) inhibiting tu-mor cell proliferation, and (5) improving antitumor immune re-sponses (Clinton 1998). However, the mechanism(s) by which thiscarotenoid might exert its biological activities and thereby mod-ulate disease processes are still unknown. In 1996, Clinton andhis coworkers suggested the occurrence of in vivo isomerizationof lycopene, since they detected higher amounts of cis-lycopenethan all-trans-lycopene in human serum and in both benign andmalignant prostate tissue. In contrast to β-carotene, few studieshave investigated the metabolism of lycopene in a biological sys-tem, and very little is known about oxidative breakdown prod-ucts of lycopene in humans. The 1st report of a metabolite inhuman plasma was that of 5,6-dihydroxy-5′,6′-dihydrolycopeneresulting from oxidation of lycopene (Khachik and others 1995,1997). It also reported that 2,6-cyclolycopene-1,5-diol A and Bare in vivo oxidative metabolites of lycopene in humans (Kingand others 1997; Bertram and others 2000). Yeum and others(2000) have carried out extensive studies on the metabolism ofβ-carotene and found that the enzymatic cleavage of β-caroteneto retinoids can occur either by an excentric or central cleavagepathway depending on the absence or presence of antioxidants,and have identified various intermediates of the excentric cleav-age of β-carotene (Tang and others 1991; Krinsky 1992; Wangand others 1992; Krinsky and others 1993). Interestingly, it wasfound that β-carotene may react with either fatty acid hydroper-oxides or their derivatives and quench alkoxyl and/or peroxylradicals (Yeum and others 1995).

Anjos Ferreira and others (2003) have investigated lycopenemetabolism using the postmitochondrial fraction of rat intestinal

mucosa. The incubation media were composed of NAD+, KCl,and DTT with or without added lipoxygenase. The addition oflipoxygenase into the incubation significantly increased the pro-duction of lycopene metabolites. The enzymatic incubation prod-ucts of 2H10 lycopene were separated using high-performance liq-uid chromatography (HPLC) and analyzed by UV/Vis spectropho-tometer and atmospheric pressure chemical ionization-massspectroscopy. They have identified 2 types of products: cleavageproducts and oxidation products. The cleavage products are likely(1) 3-keto-apo-13-lycopenone (C18H24O2 or 6,10,14-trimethyl-12-one-3,5,7,9,13-pentadecapentaen-2-one) with λmax = 365nm and m/z = 272 and (2) 3,4-dehydro-5,6-dihydro-15,15′-apo-lycopenal (C20H28O or 3,7,11,15-tetramethyl-2,4,6,8,12,14-hexadecahexaen-1-al) with λmax = 380 nm and m/z = 284.The oxidative metabolites are likely (3) 2-apo-5,8-lycopenal-furanoxide (C37H50O) with λmax = 415, 435, and 470 nm, andm/z = 510; (4) lycopene-5, 6, 5′, 6′-diepoxide (C40H56O2) withλmax = 415, 440, and 470 nm, and m/z = 568; (5) lycopene-5,8-furanoxide isomer (I) (C40H56O) with λmax = 410, 440,and 470 nm, and m/z = 552; (6) lycopene-5,8-epoxide iso-mer (II) (C40H56O) with λmax = 410, 440, 470 nm, and m/z =552; and (7) 3-keto-lycopene-5′,8′-furanoxide (C40H54O2) withλmax = 400, 420, and 450 nm, and m/z = 566. These re-sults demonstrate that both central and excentric cleavage of ly-copene occurs in the rat intestinal mucosa in the presence of soylipoxygenase.

Characterization: Isolation and Analytical MethodsVarious analytical methods have been employed in the de-

termination of lycopene in food or biological samples. Theseinclude UV-Vis spectrophotometry (Otteneder 1986), liquidchromatography connected to electrospray ionization-mass spec-troscopy (Rentel and others 1998), atomic pressure chemi-cal ionization mass spectroscopy (Hagiwara and others 1998),continuous-flow fast atom bombardment MS (van Breemen andothers 1993), subcritical fluid chromatography (Ibanez and oth-ers 1998), matrix-assisted laser desorption ionization (Kaufmannand others 1996), liquid chromatography with spectrophotomet-ric detection (Kaufmann and others 1996), HPLC (Khachik andothers 1992a), and online supercritical fluid extraction linked toHPLC using a single monolithic column (Pol and others 2004).Lycopene extraction, storage, handling, and analysis have to becarried out under controlled environmental factors not only tominimize oxidative degradation but also to avoid the introduc-tion of artifactual level of isomers. Exposure of extracted lycopeneto light should be avoided, and only gold, yellow (Landers andOlson 1986), or red lights should be used. Antioxidants suchas butylated hydroxytuolene (BHT) should be employed in ex-traction and separation solvents to control oxidation and isomer-ization reactions of lycopene (Nguyen and Schwartz 1998). Inaddition, nitrogen or argon headspace can be employed to keepexposure to atmospheric oxygen to a minimum. Saponification,using methanolic potassium hydroxide, can be performed to en-hance lycopene’s analysis by eliminating chlorophyll and lipidmaterials, which can interfere with its chromatographic elutionand detection (Kimura and others 1990).

Zechmeister and coworkers, meanwhile, made significantprogress toward the isolation of lycopene, determination of spec-trophotometric properties by means of iodine-catalyzed stereo-mutation, and establishment of the foundation for a better under-standing of lycopene’s chemical stability in terms of isomerizationand oxidation (Zechmeister and Cholnoky 1936; Zechmeisterand Tuzson 1938a, 1938b; Zechmeister and others 1941, 1943;Zechmeister and Polgar 1944; Zechmeister 1962). Many of thesebasic techniques and fundamental considerations are still in



use. Conventional spectrophotometric or HPLC methods are reli-able, but are also cumbersome and time-consuming and requireuse and disposal of hazardous organic solvents. In general, ly-copene is separated from other carotenoids using reverse-phaseC18 columns. Variations in the properties of the silica packing ma-terial in terms of particle size, porosity, carbon load, end-cappingtechnique, and polymerization can greatly influence the sensitiv-ity and selectivity of lycopene analysis (Sander and Wise 1987;Craft 1992; Epler and others 1992; Sander and others 1994). Thismay be avoided by using the method of Davis and others (2003)in which light absorbance is measured with a scanning xenonflash colorimeter/spectrophotometer to quantify lycopene con-tent in pureed translucent fruit samples. To separate lycopeneisomers, however, reversed-phase C30 stationary phase is oftenemployed to achieve superior selectivity of lycopene isomerscompared to conventional C18 reversed-phase and silica normal-phase columns (Sander and others 1994; Emenhiser and others1996). Not only do the polymerically synthesized C30 columnsprovide excellent separation of all-trans lycopene isomers fromthe cis counterpart, but they also exhibit remarkable selectiv-ity among the individual cis isomers themselves (Emenhiser andothers 1996; Rouseff and others 1996). Despite the advantages ofUV-Vis and mass spectrometric detection in routing analysis, un-equivocal structural elucidation of carotenoid stereoisomers canonly be accomplished by the use of NMR spectroscopy. Hyphen-ated techniques such as LC-NMR have been shown to be partic-ularly advantageous since they allow the direct identification ofcarotenoid stereoisomers in food as well as in physiological sam-ples (Strohschein and others 1999; Dachtler and others 2001;Glaser and others 2003). If very low levels of carotenoids needto be quantified, the use of a coulometric electrochemical detec-tor is recommended (Ferruzi and others 1998). Recently, anotherHPLC method employing different columns in series fashion hasalso been shown to resolve cis and trans lycopene isomers com-parably (Schierle and others 1997). Sixteen carotenoids, includ-ing all-trans-lutein, all-trans-lycopene, all-trans-β-carotene, andtheir 13 cis isomers were identified and resolved within 52 minwith flow-rate at 2.0 mL/min and detected at 476 nm by Lin andChen (2003). Of the various extraction solvent systems, the bestextraction efficiency of carotenoids in tomato juice was achievedby employing ethanol–hexane (4:3, v/v). Fantin and others (2007)isolated the lycopene from crude tomato extract via selective in-clusion in deoxycholic acid.

In a spectrophotometric method developed by Agarwal andRao (1998) for lycopene, estimation includes extraction of ly-copene from tomato products with a hexane-methanol-acetone(2.1:1 ratio) solvent containing 2.5% BHT as antioxidant; sub-sequently the optical density of the hexane extract is measuredspectrophotometrically at 502 nm against the hexane blank. Thismethod was found to be more convenient, faster, and less ex-pensive than the HPLC method and, thus, large numbers of sam-ples can be estimated by this method in a relatively short periodof time. Despite the above-mentioned advantages, this methodfails to differentiate between the trans and cis isomers. A rapidand inexpensive way to measure the lycopene content of certainfoods and food products naturally rich in lycopene was demon-strated by Fish and others (2002). They experimented with wa-termelons and found that the amount of lycopene in tissue canbe reliably determined and employs only 20% of the total or-ganic solvents used in conventional spectrophotometric assays.In their method, 5 mL of 0.05% (w/v) BHT in acetone, 5 mL of95% ethanol, and 10 mL of hexane are added to amber vials.Then 0.4 to 0.6 g of sample is added to the assay vial, with or-bital shaking for 15 min, after which 3 mL of deionized water areadded with further shaking for 5 min. The vials are then left tostand for 5 min for phase separation and then absorbance of the

hexane phase layer is read at 503 nm against a blank of hexanesolvent.

Vasapollo and others (2004) developed an innovative processfor the extraction of lycopene from tomatoes in the presence ofvegetable oil, using supercritical carbon dioxide as a cosolvent.The presence of cosolvent improved the yields of the lycopeneextract and had a beneficial role in the stability of the lycopenepigment. Their experiments indicated that the pretreatment of rawmaterial (drying, grinding, and screening) is necessary to obtainsignificant yields of the extractable lycopene. The best operativeconditions in terms of flow rate, time, and pressure were standard-ized as follows: 450 bar, 65 to 70 ◦C, 18 to 20 kg CO2/h, averageparticle size of the material of about 1 mm, and presence of a veg-etable oil (about 10%) as cosolvent. The highest yield of lycopenewas reported as 60% of the total amount of extractable lycopene.

Cis isomers of lycopene have distinct physical characteristicsand chemical behaviors from their all-trans counterpart. Some ofthe differences observed as a result of a trans to cis isomerizationreaction include decreased color intensity, lower melting points,smaller extinction coefficient, a shift in the λmax, and the appear-ance of a new maximum in the ultraviolet spectrum (Zechmeisterand Polgar 1944). The decrease in color intensity is of paramountimportance taken into account during quantitative analysis of ly-copene isomers to avoid underestimation. The appearance of thenew maxima in the ultraviolet region, so-called “cis-peaks,” andtheir relative intensity are useful in assigning tentative identifica-tion of lycopene isomers.

Lycopene: stability during processingIt is well known that food processing can have many effects,

not all of which result in a loss of quality and health properties.For instance, it has been recently found that the bioavailabilityof β-carotene increases as a consequence of moderate heating orthe enzymatic disruption of the vegetable’s cell wall structure. Insome cases, processing causes little or no change to the contentand activity of naturally occurring antioxidants. This is the case forsome carotenoids, such as lycopene or β-carotene, which werefound to be very heat stable even after intense or prolonged heattreatments such as sterilization processes or cooking (Nicoli andothers 1999).

Since lycopene is responsible for the red color of tomatoesand color is used as an index of quality for tomato products,minimizing the loss of lycopene throughout the production pro-cess and during storage has always been important. Traditionally,the major emphasis in the industrial processing of foods hasbeen thermal processing for preservation and microbiologicalsafety, with limited regard for nutritional quality. Over the past 3decades, there has been an increased concern for food quality,with a significant amount of work accomplished in the area ofkinetics of nutrient destruction. It is self-evident that the numberof possible degradation reactions in foodstuffs is very large andthat, in principle, several reaction mechanisms may be involved(Goula and others 2006).

Being acyclic, lycopene possesses symmetrical planarityand has no vitamin A activity; and as a highly conjugatedpolyene, it is particularly susceptible to oxidative degrada-tion. Physical and chemical factors—known to degrade othercarotenoids—including elevated temperature, exposure to light,oxygen, extremes in pH, and molecules with active surfaces thatcan destabilize the double bonds, apply to lycopene as well(Crouzet and Kanasawud 1992; Scita 1992). Cole and Kapur(1957a, 1957b) examined the kinetics of lycopene degradationby studying the effects of oxygen, temperature, and light inten-sity on the formation of its volatile oxidation products. Adding toMonselise and Berk’s (1954) report of oxidative degradation oflycopene in heat-treated tomato puree, Cole and Kapur (1957b)



reported significant losses of lycopene in serum-free tomato pulpsamples following thermal treatment at 100 ◦C in the presence ofoxygen, with or without light. The intensities of illumination andtemperature were found to be in direct correlation with lycopenedegradation in the presence of oxygen.

Undesirable degradation of lycopene affects not only the sen-sory quality of the final products but also the health benefit oftomato-based foods for the human body. Lycopene in fresh tomatofruits occurs essentially in the all-trans configuration (80% to 97%all-trans; Table 2). The main causes of tomato lycopene degrada-tion during processing are isomerization and oxidation. Isomer-ization converts all-trans isomers to cis-isomers due to additionalenergy input and results in an unstable, energy-rich station. De-termination of the degree of lycopene isomerization during pro-cessing would provide a measure of the potential health benefitsof tomato-based foods. Thermal processing (bleaching, retorting,and freezing processes) generally causes some loss of lycopene intomato-based foods. Heat induces isomerization of the all-trans tocis forms. The cis-isomers increase with temperature and process-ing time. In general, dehydrated and powdered tomatoes havepoor lycopene stability unless carefully processed and promptlyplaced in a hermetically sealed and inert atmosphere for storage.A significant increase in the cis-isomers with a simultaneous de-crease in the all-trans isomers can be observed in the dehydratedtomato samples using the different dehydration methods. Frozenfoods and heat-sterilized foods exhibit excellent lycopene stabil-ity throughout their normal temperature storage shelf life (Shi andLe Maguer 2000; Xianquan and others 2005). The bioavailabil-ity of cis-isomers in food is higher than that of all-trans isomers(Schieber and Carle 2005). Lee and Chen (2002) studied the sta-bility of lycopene during heating and illumination. They carriedout various pretreatment steps to the all-trans lycopene standard,which included dissolving the lycopene standard in hexane andevaporating to dryness under nitrogen in vials, after which a thinfilm formed at the bottom surface. The resulting lycopene washeated at 50, 100, and 150 ◦C or illuminated at a distance of30 cm with illumination intensity in the range of 2000 to 3000lux (25 ◦C) for varied lengths of time (up to 100 h for heatingand 5 d for illumination). At 50 ◦C, the isomerization dominatedin the first 9 h; however, degradation was favored afterward. At100 and 150 ◦C, the degradation proceeded faster than the iso-merization, whereas during illumination, isomerization was themain reaction. At 25 ◦C, storage of apple juice for 9 mo resultsin a 60% loss of quercetin and a total loss of procyanidins, de-spite the fact that polyphenols are more stable in fruit juices thanis vitamin C (Spanos and others 1990; Miller and others 1995).Tomatoes lose 80% of their initial quercetin content after boilingfor 15 min, 65% after cooking in microwave oven, and 30% afterfrying (Crozier and others 1997). Steaming of vegetables, whichavoids leaching, is preferable.

Table 2 --- Isomer composition of tomato products.

Product Percent trans Reference

Raw tomato 90 Clinton and others (1996)Tomato soup 79Tomato paste 91Raw tomato 95 Gartner and others (1997)Tomato paste 93 Nguyen and Schwartz (1998)Tomato juice 94Ketchup 94Pizza sauce 96Tomato paste 96 Schierle and others (1997)Canned tomatoes 84

In other lycopene-containing fruits such as papaya slices, food-processing operations such as freezing and canning lead to a sig-nificant decrease in total carotenoid content, of which lycopeneis a major component (Cano and others 1996). In contrast, a num-ber of studies on the thermal stability of carotenoids in processedfruits and vegetables have found that hydrocarbon carotenoidssuch as lycopene, α-carotene, and β-carotene are relatively heat-resistant (Khachik and others 1992a, 1992b). Isomerization offruit and vegetable carotenoids as a result of thermal treatmentsduring food processing and preparation is well known, especiallyfor β-carotene (Panalaks and Murray 1970; Sweeney and Marsh1971; Tsukida and others 1981; Bushway 1985; Quackenbush1987; Chandler and Schwartz 1988; Lessin and others 1997).According to the findings of Lessin and others (1997), canning offresh tomatoes increases the β-carotene cis isomer content from12.9% to 31.2%. Nguyen and Schwartz (1998) demonstratedthat, unlike β-carotene, little isomerization of all-trans lycopeneto cis- lycopene was noted with thermal processing (Table 3).Heating tomato juice (Stahl and Sies 1992) and bench-top prepa-ration of a spaghetti sauce from canned tomatoes (Schierle andothers 1997) was shown to increase the level of lycopene cis-isomers. Even dehydration, which is performed at high heat overrelatively long periods of time, only results in small increasesin cis-lycopene isomers in tomato products (Table 3). However,Khachik and others (1992b) indicated that common heat treat-ments during food preparation such as microwaving, boiling,steaming, and stewing did not significantly alter carotenoid dis-tribution in green vegetables. Other studies have also reportedthe levels of lycopene cis-isomers in thermally processed tomatoproducts to be low (Clinton and others 1996).

The experimental data from our laboratory studies (unpub-lished results) have recently confirmed that baking results in asignificant increase in lycopene content of baked pizza whencompared to unbaked pizza, making it more bioavailable,and when packed under different gas atmospheres (modifiedatmospheres—CO2, N2, and their mixtures) and stored at refrig-eration conditions significantly helps in retaining the natural redcolor (lycopene) of both types of pizza samples during storage.

Lycopene is more stable in native tomato fruit tissues and ma-trices than in isolated or purified form (Simpson and others 1976)as a result of the protective effects of cellular constituents suchas water. Therefore, care must be taken to minimize the loss oflycopene through oxidation or isomerization during extraction,storage, handling, and analysis to accurately account for cause–effect changes. In lycopene context, food processing is in facta value-added step, in that more lycopene becomes bioavail-able following thermal treatment. Heating of tomato juice wasshown to result in an improvement in uptake of lycopene in hu-mans (Stahl and Sies 1992). Gartner and others (1997) showed

Table 3 --- Influence of processing on lycopene isomeriza-tion in foods.

PercentLycopene source trans Reference

Fresh tomato 100 Shi and Le Maguer (2000)Vac-dried 89.9Air-dried 84.4Fresh tomato 95.8 Nguyen and Schwartz (1998)Fresh tomato, heated 89.3

200 ◦C, 45 minTomato paste 92.6 Schierle and others (1997)Tomato paste, heated 83.4

70 ◦C, 3 h



that tomato paste, a processed product, has more bioavailable ly-copene than fresh tomatoes when both are consumed along withcorn oil. This may be attributed to its release from the plant tis-sue matrix, weakening of lycopene–protein complexes resultingfrom heat-induced cellular disruption and heat-induced trans- tocis-isomerization.

A study was conducted by Agarwal and others (2001) to evalu-ate the stability, isomeric form, bioavailability, and in vivo antiox-idant properties of lycopene because tomatoes undergo extensiveprocessing and storage before consumption. Total lycopene andisomers were measured by spectrophotometer and HPLC, respec-tively. Lycopene content of tomatoes remained unchanged duringthe multistep processing operations for the production of juice orpaste and remained stable for up to 12 mo of storage at ambi-ent temperature. Moreover, subjecting tomato juice to cookingtemperatures in the presence of corn oil resulted in the forma-tion of the cis isomeric form, which was considered to be morebioavailable. Lycopene was absorbed readily from the dietarysources. Serum lipid and low-density lipoprotein oxidation weresignificantly reduced after the consumption of tomato productscontaining lycopene.

Hadley and others (2002) stated that carotenoids are stronglybound to intracellular macromolecules in many foods, and ab-sorption, therefore, may be limited unless released from the foodmatrix. Heating tomato juice was shown to improve the uptakeof lycopene in humans. These observations seem to be the resultof thermal weakening and disruption of lycopene–protein com-plexes, rupturing of cell walls, and/or dispersion of crystallinecarotenoid aggregates. Similarly, various food processing opera-tions such as chopping and pureeing, which result in a reductionin physical size of food particles, will also enhance lycopenebioavailability. Lycopene bioavailability was recently studied af-ter ingesting a single dose of fresh tomatoes or tomato paste bymeasuring carotenoid concentrations in the chylomicron fractionof the systemic circulation. Each source of lycopene (23 mg) wasconsumed with 15 g of corn oil. Tomato paste was found to yielda 2.5-fold greater total all-trans lycopene peak concentration anda 3.8-fold greater area under the curve than fresh tomatoes. Whencompared with fresh tomatoes, ingestion of tomato paste resultedin a significantly higher area under the curve for cis lycopeneisomers. Recent data in their laboratory from a pilot clinical trialof lactating women showed greater concentration of lycopenein human milk for those consuming tomato sauces compared tofresh tomatoes. These observations support the conclusion thatfood processing and cooking enhance lycopene bioavailability.According to Zimmerman (2002), cooked tomato products (evenpizza) pack more bioavailable lycopene than the raw fruit (4.5 mglycopene per 100 g of frozen pizza).

Labrador and others (1999) studied the effect of processingtechniques on the color and lycopene content of tomato saucesfor pizza during frozen storage by preparing different tomatosauces for pizza topping in the pilot plant. They determined byanalytical quantification the color changes in commercial prod-ucts during frozen storage, and they also determined the im-pact of processing method on the color stability of the sauces,comparing 2 common cooking processes. Sauces prepared inan open stirred kettle and in a tubular pasteurizer were differ-ent in terms of color attributes and lycopene content. The saucefrom the kettle had significantly better initial color, but it showeda faster change in color attributes and lycopene content dur-ing storage, indicating lower stability. Mayer-Miebach and Spieβ(2003) studied the influence of cold storage and blanching on thecarotenoid content of Kintoki carrots, containing about 9 mg oflycopene on a wet weight basis, and concluded that high avail-ability and stability of lycopene are achieved in carrot products

after blanching at high temperatures (T = 90 ◦C) and oxygen-freeconditions.

Lycopene: Tissue Distribution and ConcentrationLycopene levels in various human organs and tissues and their

uptake from the diet into these tissues have been studied for manyyears (Parker 1988; Kaplan and others 1990; Schmitz and others1991; Nierenberg and Nann 1992). It is the most predominantcarotenoid in human plasma. Allen and others (2002) demon-strated that tomato consumption increases lycopene isomer con-centrations in breast milk and plasma of lactating women. Its levelis affected by several biological and lifestyle factors (Erdman andothers 1993; Rao and Agarwal 1999). Consumption of raw andprocessed tomatoes varied by sociodemographic characteristics,and determinants of plasma lycopene concentration were age,plasma cholesterol concentration, and smoking habit (Re and oth-ers 2003). Owing to their lipophilic nature, lycopene and othercarotenoids are found to concentrate in low-density and very-low-density lipoprotein fractions of the serum (Clinton 1998). Ahigher percentage of the cis form of lycopene is present in tis-sues than is the trans. This may be due to better absorption ofcis-lycopene or an increased tissue uptake (Erdman and others1988; Stahl and Sies 1992). Lycopene is known to accumulatein human tissues, and its distribution in tissues is not uniform.The findings were summarized by Stahl and Sies (1996) and arepresented in Table 4, which depicts lycopene variation betweendifferent tissues. Generally, lycopene is most prominent in thetestes, adrenal glands, liver, and prostate tissues and present inrelatively low concentrations in kidney, lungs, and ovary tissues(Kaplan and others 1990; Schmitz and others 1991; Nierenbergand Nann 1992; Stahl and others 1992). According to the ob-servations and findings of Boileau and others (2002), lycopene,the predominant carotenoid in tomatoes, is among the majorcarotenoids in serum and tissues of Americans. Although about90% of the lycopene in dietary sources is found in the linear, all-trans conformation, human tissues contain mainly cis-isomers.Several research groups have suggested that cis-isomers of ly-copene are better absorbed than the all-trans form because ofthe shorter length of the cis-isomer, the greater solubility of cis-isomers in mixed micelles, and/or as a result of the lower ten-dency of cis-isomers to aggregate. Work with ferrets, a speciesthat absorbs carotenoids intact, has demonstrated that, whereasa lycopene dose and stomach and intestinal contents contained6% to 18% cis-lycopene, the mesenteric lymph secretions con-tained 77% cis-isomers. The ferret studies support the hypothesisthat cis-isomers are substantially more bioavailable than all-translycopene. In vitro studies suggest that cis-isomers are more solu-ble in bile acid micelles and may be preferentially incorporatedinto chylomicrons. The implications of these findings are not yetclear. Rats appear to accumulate lycopene in tissues within theranges reported for humans, suggesting that they can be usedto study effects of lycopene isomers on disease processes. In-vestigations are under way to determine whether there are bio-logical differences between all-trans and various cis-isomers oflycopene regarding its antioxidant properties or other biologicalfunctions.

The bioavailability of dietary lycopene is dependent upon sev-eral factors, such as the matrix in which lycopene is incorporated,physical state of lycopene, particle size before and after masti-cation, digestive processes (Johnson 1998), and the presence ofdietary fiber, which has been shown to interfere with micelle for-mation (Rock and Swenseid 1992). Also, lipid concentrations aswell as the type of lipid involved may regulate the amount of ly-copene absorbed from the gut into the plasma (Bohm 2002). At



least 18 different carotenoids have so far been identified in hu-man serum, with β-carotene and lycopene being the prominentcarotenoids (Krinsky and others 1990; Khachik and others 1992a,1995). Similarly, Peng and Peng (1992) found lycopene to be thepredominant carotenoid present in mucosal cells at 15.54 ng/106

cells. Lycopene has been shown to exist in several geometricalconfigurations in human plasma and in a variety of tissue sam-ples, where the cis-isomer content ranges from 50% to 88% ofthe total lycopene level (Krinsky and others 1990; Schmitz andothers 1991; Stahl and others 1992; Emenhiser and others 1996;Clinton and others 1996). Tissue-specific lycopene distributionmay be important in the role of this antioxidant. However, unlikeother carotenoids, lycopene levels in serum or tissues do not cor-relate well with overall intake of fruits and vegetables (Michaudand others 1998; Freeman and others 2000).

Recently, Shi and others (2008) investigated the effects of heat-ing and exposure to light on lycopene stability by exposing tomatopuree to different temperature treatments (60, 80, 100, 120 ◦C,1 to 6 h) and exposure to light (light intensity similar to normalindoor condition, 1 to 6 d). The results showed that 60 and 80 ◦Cheating favored the isomerization of lycopene. Heating treatmentat 120 ◦C and long-time heating treatment at 100 ◦C improvedthe extraction of lycopene from puree matrix. Color change oftomato puree was inconsistent because the measured value wasaffected by the different extractability of lycopene in puree ma-trix. Exposure to light caused no significant change to total andall-trans lycopene, although significant loss of cis-isomer.

Functional Lycopene: Role in Human HealthThe interest in the possible anticancer properties of

carotenoids, and more recently lycopene itself, is based not onlyon a sound scientific basis but also on a wealth of epidemiologicaldata from around the world. The strength of the evidence is suchthat the U.S. Natl. Research Council of the Academy of Sciences(1989), the NCI (1987), and the World Cancer Research Fund, theAmerican Inst. for Cancer Research (1997) have all recommendedincreasing dietary intake of citrus fruits, cruciferous vegetables,green and yellow vegetables, and fruits and vegetables high invitamins A and C to lower cancer risk. Similar recommendationshave been made by the UKDoH (1999) and by the WHO (1990).

Lycopene is one of the most potent antioxidants (Di Mascioand others 1989; Miller and others 1996; Mortensen andSkibsted 1997; Woodall and others 1997), with a singlet-oxygen-quenching ability twice as high as that of β-carotene and 10 timeshigher than that of α-tocopherol (Di Mascio and others 1989). Ithas attracted attention due to its biological and physicochemicalproperties, especially related to its effects as a natural antioxi-dant. This makes its presence in the diet of considerable inter-est. Increasing clinical evidence supports the role of lycopeneas a micronutrient with important health benefits, because it ap-pears to provide protection against a broad range of epithelialcancers. In the area of food and phytonutrient research, nothinghas been hotter in the last 5 y than studies on the lycopene intomatoes (Shi and Le Maguer 2000). Lycopene has gained muchinterest in the recent past as more evidence has continued to sug-gest that it may provide protection against degenerative diseasesinfluenced by free radical reactions, such as cancer and coro-nary heart disease (Kun and others 2006). Levy and others (1995)showed lycopene to be a more potent inhibitor of human cancercell proliferation than either α-carotene or β-carotene. In anothercase-control study, a high intake of fresh tomatoes was linked toa protective effect of the digestive tract against the risk of cancer(Franceschi and others 1994). A high tomato intake in an elderlyAmerican population was similarly associated with a 50% reduc-

tion in mortality from cancer at all sites (Colditz and others 1985).Tomato lycopene extract supplementation decreases insulin-likegrowth factor-I levels in colon cancer patients. Epidemiologicalstudies have shown that high serum levels of insulin-like growthfactor-I are associated with an increased risk of colon and othertypes of cancer (Walfisch and others 2007).

The biochemical mechanisms underlying the health-promotingroles are not fully understood, although the antioxidative activityof lycopene (Rao and Agarwal 1999), which has been shown to bea potent protector against oxidative damage to DNA, protein andlipids, is thought to be primarily responsible. Other activities oflycopene such as modulation of cell–cell communication (Zhangand others 1991), inhibition of cell proliferation (Levy and others1995), and resistance to bacterial infections may also be involved.Recent studies suggest that chronic diseases, including cancerand cardiovascular disease, are associated with inflammation andcoagulation. Jorge (2001) and Zimmermann and others (1999)have proposed that cardiovascular diseases such as atherosclero-sis and other coronary syndromes are induced via inflammatorypathways. The beneficial effects of some therapies, such as 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors andangiotensin converting enzyme (ACE) inhibitors, have been at-tributed in part to the inhibition of inflammation. Yaping andothers (2003) evaluated the anti-inflammatory and anticoagulantactivities of lycopene using mouse models. Lycopene was pro-vided in the form of oleoresin. The croton oil-induced mouse earedema model was used to study the anti-inflammatory activity,while the glass slide method was used to evaluate the anticoag-ulant activity. Administration of lycopene for 4 d was associatedwith decreased swelling of the treated ear with efficiency com-parable to that of amoxicillin, a well-known inflammatory agent.In addition, lycopene increased the coagulation time. These re-sults suggested the health-promoting roles of lycopene with itsanti-inflammatory and anticoagulant activities.

Scolastici and others (2007) investigated the antigeno-toxic/antimutagenic effects of lycopene in Chinese hamster ovarycells (CHO) treated with hydrogen peroxide, methylmethane-sulphonate (MMS), or 4-nitroquinoline-1-oxide (4-NQO). Ly-copene (97%), at final concentrations of 10, 25, and 50 µM, wastested under 3 different protocols: before, simultaneously, and af-ter the treatment with the mutagens. Comet and cytokinesis-blockmicronucleus assays were used to evaluate the level of DNAdamage. Data showed that lycopene reduced the frequency ofmicronucleated cells induced by the 3 mutagens. However, thischemopreventive activity was dependent on the concentrationsand treatment schedules used. Similar results were observed inthe comet assay, although some enhancements of primary DNAdamage were detected when the carotenoid was administered af-ter the mutagens. Their findings confirmed the chemopreventiveactivity of lycopene, and showed that this effect occurs underdifferent mechanisms.

Colorectal cancerA study conducted by Erhardt and others (2003) revealed that in

patients with colorectal adenomas, a type of polyp that is the pre-cursor for most colorectal cancers, blood levels of lycopene were35% lower compared to study subjects with no polyps. Bloodlevels of β-carotene also tended to be 25.5% lower, althoughaccording to researchers, this difference was not considered tobe significant. In their final (multiple logistic regression) analy-sis, only low levels of plasma lycopene (less than 70 µg/L) andsmoking increased the likelihood of colorectal adenomas, butthe increase in risk was quite substantial: low levels of lycopeneincreased risk by 230% and smoking by 302%.



Prostate cancerThe role of diet and dietary supplements in the development

and progression of prostate cancer represents an increasingly fre-quent topic of discussion (Barber and Barber 2002). The pub-lic and the biomedical community are increasingly aware ofassociations between tomato products, lycopene, and health out-comes. Scientists from many disciplines ranging from epidemiol-ogy, clinical medicine, nutrition, agriculture, and molecular andcell biology have published peer-reviewed studies providing in-triguing data suggesting that tomato products and the carotenoidlycopene may be involved in cancer prevention, reducing the riskof cardiovascular disease, and limiting the morbidity or mortalityof other chronic diseases (Miller and others 2002). Carotenoidsmay react with oxygen-free radicals by either transfer of the un-paired electron leaving the carotenoid in an excited triplet state,the excess energy being dissipated as heat, or by “bleaching” ofthe carotenoid. The former leaves the carotenoid intact and there-fore able to be involved in numerous cycles of free radical scav-enging, and the latter results in decomposition of the carotenoid.Fortunately, it is the former that predominates, and the efficiencyof this process seems to be related to the number of double bondsincorporated in the carotenoid structure. Interest has been height-ened in lycopene, in particular, as it has a large number of doublebonds and thus has been found to be the most potent scavengerof oxygen-free radicals of all the carotenoids (Miller and others1996; Rao and others 2003). Lycopene has been demonstrated tonot only scavenge oxygen-free radicals species, for example, per-oxyl radicals, but also interact with reactive oxygen species suchas hydrogen peroxide and nitrogen dioxide (Bohm and others1995; Woodall and others 1997) and in this manner protect cellsfrom oxidative damage. Interestingly, lycopene was found to betwice as efficient as β-carotene in scavenging for nitrogen dioxide(Tinkler and others 1994; Bohm and others 1995; Woodall andothers 1997). Lycopene has also been demonstrated to have otherpossible anticancer properties particularly relating to modulationof intercellular communication and alterations in intracellular sig-naling pathways (Stahl and Sies 1996). These include an upreg-ulation in intercellular gap junctions (Zhang and others 1992),an increase in cellular differentiation (Bankson and others 1991),and alterations in phosphorylation of some regulatory proteins(Matsushima-Nishiwaki 1995). Little is known regarding the roleor indeed importance of these effects in vivo; however, lycopenehas been demonstrated to be significantly more efficient than anycarotene in inhibiting insulin-like growth factor type 1 (IGF1) in-duced proliferation of a number of tumor cell lines (Levy andothers 1995) and decrease the occurrence of both spontaneousand chemically induced mammary tumors in animal models (Na-gasawa and others 1997; Sharoni and others 1997). In prostatecancer, in particular, a study has demonstrated inhibition of cellline proliferation in the presence of physiological concentrationsof lycopene in combination with α-tocopherol (Pastori and others1998).

Lycopene is present in the human prostate at significant con-centrations, and recent studies suggested that men with higherconcentrations of blood lycopene experience a lower risk ofprostate carcinoma (Clinton 1999). In a Harvard Health Profes-sionals Follow-Up Study, in which the relationship between in-take of various carotenoids, retinal, fruits and vegetables, andthe reduced risk of prostate cancer was examined for a cohortof 47894 male subjects, Giovannucci and others (1995) con-cluded that consumption of fresh tomatoes, tomato sauce, andpizza, which account for the bulk of dietary lycopene intake,is significantly related to a lower incidence of prostate cancer.Prior to the latter study, accumulated human epidemiological ev-idence indicated that diets high in tomatoes might reduce the riskof developing cervical, colon, oesophageal, rectal, and stomach

cancers (Bjelke 1974; Cook-Mozaffari and others 1979; Tajimaand Tominaga 1985; Batieha and others 1993; Ramon and others1993; Potischman and others 1994; Giovannucci 2002).

Pizza has been favorably related to reducing the risk of prostatecancer in North America. Scanty information, however, is avail-able on sex hormone-related cancer sites. Silvano and others(2006) studied the role of pizza consumption on the risk of breast,ovarian, and prostate cancers using data from 3 hospital-basedcase-control studies conducted in Italy between 1991 and 2002.These included 2569 women with breast cancer, 1031 with ovar-ian cancer, 1294 men with prostate cancer, and a total of 4864controls. Compared with nonpizza eaters, the multivariate oddsratios for eaters were 0.97 (95% confidence interval [CI] 0.86to 1.10) for breast, 1.06 (95% CI 0.89 to 1.26) for ovarian, and1.04 (95% CI 0.88 to 1.23) for prostate cancer. Correspondingestimates for regular eaters (more than 1 portion per week) were0.92 (95% CI 0.78 to 1.08), 1.00 (95% CI 0.80 to 1.25), and 1.12(95% CI 0.88 to 1.43), respectively. Our results do not show arelevant role of pizza on the risk of sex hormone-related can-cers. The difference with selected studies from North Americasuggests that dietary and lifestyle correlates of pizza eating varyamong different populations and social groups.

Tomatoes have been shown to be helpful in reducing the riskof prostate cancer. A 14-mo study conducted by Boileau and oth-ers (2003) underscores the importance of a healthy whole foodsdiet rich in tomatoes in the prevention of prostate cancer. In thisstudy, rats fed lycopene-rich diet and treated with N-methyl-N-nitrosourea (a carcinogen) and testosterone to induce prostatecancer had a similar risk of death from prostate cancer as rats feda control diet. In contrast, rats fed whole tomato powder were26% less likely to die of prostate cancer. By the end of the study,80% of the control group and 72% of the rats fed lycopene hadsuccumbed to prostate cancer, while only 62% of the rats fedwhole tomato powder had died. Researchers concluded this wasdue to the fact that tomatoes contain not merely lycopene butalso a variety of protective phytochemicals, and suggested thatthe lycopene found in human prostate tissue and the blood ofanimals and humans who remain free of prostate cancer may in-dicate exposure to higher amounts of not just lycopene but alsoother compounds working in synergy with it.

A meta-analysis of 21 studies by Etminan and others (2004)confirms that eating tomatoes, especially cooked tomatoes, pro-vides protection against prostate cancer (meta-analyses are con-sidered the gold standard in medical research since, by combin-ing the results of numerous studies, they integrate the results thatoccurred in different settings and include a much larger group ofpeople, so they are thought to provide a more accurate assess-ment). When the data from all 21 studies were combined, menwho ate the highest amounts of raw tomatoes were found to havean 11% reduction in risk for prostate cancer. Those eating the mostcooked tomato products fared even better with a 19% reductionin prostate cancer risk. Although the epidemiological evidence ofthe role of lycopene in cancer prevention is persuasive, this roleremains to be proven. There are few human intervention trials in-vestigating the effectiveness of lycopene in lowering cancer risk.Most of the researchers have investigated the effects of tomato ortomato product (lycopene) supplementation on oxidative damageto lipids, proteins, and DNA (Pool-Zobel and others 1997; Agar-wal and Rao 1998; Rao and Agarwal 1998). A preliminary reporthas indicated that tomato extract supplementation in the form ofoleoresin capsules lowers the levels of prostate-specific antigenin patients with prostate cancer (Kucuk and others 2002).

Pancreatic cancerOne of the deadliest cancers, pancreatic cancer progresses so

rapidly that individual with the disease who are participating in



studies often die before their interviews can be completed—so thebenefits noted in the following study of a diet rich in tomatoesand tomato-based products are especially significant.

In a 3-y Canadian study done by Nkondjock and others(2005), 462 persons with pancreatic cancer were age- andgender-matched with 4721 individuals free of the disease. Af-ter adjustment for age, province, body mass index, smoking,educational attainment, dietary folate, and total caloric in-take, the data showed men consuming the most lycopene, acarotenoid provided mainly by tomatoes, had a 31% reductionin their risk of pancreatic cancer. Among persons who had neversmoked, those whose diets were richest in β-carotene or totalcarotenoids reduced the risk of pancreatic cancer by 43% and42%, respectively. The researchers identified the unique mecha-nism through which lycopene protects against cancer: activatingcancer-preventive phase II enzymes. When the researchers incu-bated breast and liver cancer cells with lycopene, the carotenoidtriggered the production and activity of the phase II detoxifica-tion enzymes [NAD(P)H: quinone oxidoreductase (NQ01) andglutamylcysteine synthetase (GCS)]. Lycopene ramped up pro-duction and activity of these protective enzymes by causing theexpression of a reporter gene called luciferase that then activatedthe “antioxidant response element” in other genes that encodethe enzymes, thus causing the genes to direct increased enzymeproduction. In contrast, other carotenoids, including β-carotene,astaxanthin, and phytoene, did not have this effect. Since muchepidemiological evidence indicates that lycopene acts synergisti-cally with other phytochemicals to give tomatoes their protectiveeffects, and recent studies have shown that eating tomato prod-ucts prevents cancer more effectively than taking lycopene alone,the researchers concluded that other carotenoids stimulate phaseII enzymes via different pathways from that used by lycopene.

Coronary heart diseasesThe lycopene in tomatoes may also provide cardiovascular

benefits. Epidemiological studies have also supported the hypoth-esis that consumption of heat-processed tomatoes may reducethe risk of coronary heart diseases as the lycopene interferes pas-sively with oxidative damage to DNA and low-density lipopro-teins (Ojima and others 1993; Diaz and others 1997; Gester 1997;Clinton 1998; Weisburger 1998; Hadley and others 2003). Ly-copene’s ability to act as an antioxidant and scavenger of freeradicals that are often associated with carcinogenesis is poten-tially a key to the mechanism for its beneficial effects on humanhealth (Khachik and others 1995). Researchers suggest that inaddition to its inverse association with various cancers, a highdietary consumption of lycopene may play a role in cardiovas-cular disease prevention. They tracked 39876 middle-aged andolder women who were free of both cardiovascular disease andcancer when the study began. During more than 7 y of follow-up,those who consumed 7 to 10 servings each week of lycopene-rich foods (tomato-based products, including tomatoes, tomatojuice, tomato sauce, and pizza) were found to have a 29% lowerrisk of CVD compared to women eating less than 1.5 servingsof tomato products weekly. Women who ate more than 2 serv-ings each week of oil-based tomato products, particularly tomatosauce and pizza, had an even better result, a 34% lower risk ofCVD.

Another study, this one conducted in Europe, also suggests thatenjoying tomatoes raw or in the form of tomato sauce or pasteseveral times each week is a delicious way to protect your car-diovascular system. Visioli and others (2003) reported that whena group of 12 healthy women ate enough tomato products to pro-vide them with 8 mg of lycopene daily for a period of 3 wk, theirLDL cholesterol was much less susceptible to free radical oxida-tion, the 1st step in the formation of atherosclerotic plaque forma-

tion and a major risk factor for cardiovascular disease. Lipophiliccompounds contained in tomato can prevent cardiovascular dis-eases by modulating the atherogenic processes in vascular en-dothelium mediated by oxidized low-density lipoproteins (LDLs).Balestrieri and others (2004) investigated that lycopene in associ-ation with α-tocopherol or tomato lipophilic extracts enhancesacyl-platelet-activating factor biosynthesis in endothelial cellsduring oxidative stress.

Lycopene’s protective effects against oxidative stress were alsoillustrated when human skin is irradiated with UV light. Lycopenewas found to be preferentially destroyed relative to β-carotene,suggesting either a more active or a more protective role (Ribayo-Mercado and others 1995).

In a multicenter case-control study, the relation between an-tioxidant status and acute myocardial infarction was evalu-ated (Kohlmeier and others 1997). Subjects were recruited from10 European countries to maximize the variability in exposurewithin the study. Adipose tissue antioxidant levels, which are bet-ter indicators of long-term exposure than blood antioxidant levels,were used as markers of antioxidant status. Biopsy specimens ofadipose tissue were taken directly after the infarction and wereanalyzed for various carotenoids. After adjustment for a range ofdietary variables, only lycopene levels and not β-carotene lev-els were found to be protective. A study from Johns HopkinsUniv., Baltimore, showed that smokers with low levels of cir-culating carotenoids were at increased risk for subsequent my-ocardial infarction (Handelman and others 1996). Lower bloodlycopene levels were also found to be associated with increasedrisk for and death from coronary artery disease in a populationstudy comparing Lithuanian and Swedish cohorts with differentrates of death from coronary artery disease (Kristenson and others1997).

FDA Health Claims and LabelingFunctional foods can have a “brand” or label that claims to im-

prove health and are regulated by the U.S. Food and Drug Admin-istration (USFDA). An USFDA-approved health claim is grantedwhen valid, very strong scientific evidence exists and scientificexperts agree about a relationship between a food substance anda disease or health-related condition. Approved foods have con-vincingly demonstrated the benefits of their intended purposewhen consumed at sufficient levels on a regular basis and as partof a generally well balanced and healthful diet (Herring and Al-brecht 2005). With notification to the FDA, a food producer alsomay use a health claim if based on current, published authorita-tive statements from federal scientific bodies such as Centers forDisease Control and Prevention or Natl. Inst. of Health. Qualifiedhealth claims are also allowed by the FDA based on the weightof the scientific evidence for the food–disease relationship. Fol-lowing passage of the Nutrition Labeling and Education Act of1990, the FDA established general requirements for health claimsconcerning the relationship between a nutrient and a disease orhealth-related condition (USFDA 1993). These requirements in-cluded an FDA review of the scientific evidence supporting ahealth claim prior to its use on food and dietary supplement la-bels. In July 2003, the FDA established an evidence-based ap-proach to evaluate potential health claims and developed a sys-tem of qualifying language to communicate the relative strengthof the scientific evidence (Anonymous 2004). Anderson and oth-ers (2007) investigated a case study in implementing the FDA’sinterim guidance for qualified health claims for consumption oftomatoes, tomato products, and/or lycopene and risk of prostatecancer but did not find the sufficient evidence to support a healthclaim for a relationship between lycopene supplementation andreduced risk of prostate cancer. Kirsh and others (2006) have



done a perspective study of lycopene and tomato product in-take and risk of prostate cancer, and their study also does notsupport the hypothesis that greater lycopene/tomato product con-sumption protects from prostate cancer and concluded that evi-dence for protective associations in subjects with a family historyof prostate cancer requires further corroboration. In November2005, the FDA issued its response and concluded that “thereis no credible evidence to support a qualified health claim fortomato lycopene; tomatoes and tomato products, which containlycopene; lycopene in tomatoes and tomato products; lycopenein fruits and vegetables, including tomatoes and tomato prod-ucts, and lycopene as a food ingredient, a component of food,or as a dietary supplement and reduced risk of prostate cancer”(USFDA 2005). According to the FDA, there was insufficient ev-idence to suggest that lycopene by itself reduces risk of prostatecancer. The FDA put forward following health claim “very limitedand preliminary scientific research suggests that eating one-halfto one cup of tomatoes and/or tomato sauce a week may re-duce the risk of prostate cancer. FDA concludes that there is littlescientific evidence supporting this claim.” The FDA determinedthat it was scientifically inappropriate to extrapolate the resultsobtained from studies using individuals already diagnosed withprostate cancer to individuals who did not have the diseases.To do so, “the available scientific evidence must demonstratethat: (1) the mechanism(s) for the mitigation or treatment effectsmeasured in the diseased populations are the same as the mech-anism(s) for risk reduction effects in non-diseased populations;and (2) the substance affects these mechanisms in the same wayin both diseased people and healthy people” (USFDA 2005). TheFDA determined that such evidence was not available.

The FDA would not draw any conclusions from the review arti-cles, meta-analyses, or abstracts because they did not contain suf-ficient information on the individual studies that they reviewed.Furthermore, the FDA stated that it “did not consider the animalor in vitro studies as providing any supportive information aboutthe substance-disease relationship because such studies cannotmimic the normal physiology that may be involved in the riskreduction of any type of cancer, nor can the studies mimic thehuman body’s response to the consumption of tomato lycopene;tomatoes and tomato products, which contain lycopene” (USFDA2005). Several consumer-based research studies to assess the ef-fectiveness of various ways of communicating the level of scien-tific support for health claims on food labels have been conductedby the FDA (Derby and Levy 2005). The results of these studiessuggest that it is very difficult to provide health claims that enableconsumers to differentiate between varying levels of scientific un-certainty.

Lycopene Action: Synergy with Other Tomato NutrientsIn addition to the center-stage phytonutrient, lycopene, toma-

toes are packed with traditional nutrients that have been shownin many studies. For example, tomatoes are an excellent sourceof vitamin C and vitamin A, the latter notably through its concen-tration of carotenoids, including β-carotene. These antioxidantstravel through the body neutralizing dangerous free radicals thatcould otherwise damage cells and cell membranes, escalatinginflammation and the progression or severity of atherosclerosis,diabetic complications, asthma, and colon cancer (Erhardt andothers 2003). In fact, high intakes of these antioxidants havebeen shown to help reduce the risk or severity of all these ill-nesses. In addition, tomatoes are a very good source of fiber,which has been shown to lower high cholesterol levels, keepblood sugar levels from getting too high, and help prevent coloncancer. A cup of fresh tomato will provide 57.3% of the dailyvalue (DV) for vitamin C, plus 22.4% of the DV for vitamin A, and

7.9% of the DV for fiber (Yamamoto and others 2003). Polyphe-nols are abundant micronutrients in our diet, and evidence fortheir role in the prevention of degenerative diseases such as can-cer and cardiovascular diseases is emerging. The health benefitsof polyphenols depend on the amount consumed and on theirbioavailability (Manach and others 2004). Scientists have cre-ated genetically modified tomatoes with boosted levels of natu-ral chemicals called flavonols, which are powerful antioxidants.Flavonols are the most ubiquitous flavonoids in foods, and themain representatives are quercetin and kaempferol. They are gen-erally present at relatively low concentrations of approximately15 to 30 mg/kg fresh weight. These flavonols accumulate in theouter and aerial tissues (skin) because their biosynthesis is stimu-lated by light. Marked differences in concentration exist betweenpieces of fruit on the same tree and even between different sidesof a single piece of fruit, depending on the exposure of light (Priceand others 1995). This phenomenon also accounts for the higherflavonol content of cherry tomatoes than of standard tomatoes,because they have different proportions of skin to whole fruit(Manach and others 2004). These substances “mop up” destruc-tive molecules known as free radicals, the natural waste productsof our metabolism, which can damage cells and DNA and hastenaging. By inserting a Petunia gene into the tomato, the British andDutch researchers increased the content of flavonols of the fruit78 times. Flavonols are most accessible from pureed and cookedtomato, so the health potential for pizza and other tomato-basedfoods is obvious. Identifying and isolating the thousands of pro-tective compounds in fruits and vegetables, and using them tocreate “functional” foods, soon promises to become a lucrativeindustry (Anonymous 2001).

Apart from lycopene, tomatoes are a very good source of potas-sium and a good source of niacin, vitamin B6, and folate. Niacinhas been used for years as a safe way to lower high cholesterol lev-els. Diets rich in potassium have been shown to lower high bloodpressure and reduce the risk of heart disease. Vitamin B6 and fo-late are both needed by the body to convert a potentially danger-ous chemical called homocysteine into other, benign, molecules.High levels of homocysteine, which can directly damage bloodvessel walls, are associated with an increased risk of heart attackand stroke (Sesso and others 2004).

The folate in tomatoes can also help to reduce the risk of coloncancer. In addition, tomatoes are a good source of riboflavin,which has been shown to be helpful in reducing the frequency ofmigraine attacks in those who suffer from them (Sanchez-Morenoand others 2004). A sufficient intake of chromium, a mineral ofwhich tomatoes are a good source, has been shown to help dia-betic patients keep their blood sugar levels under control. In ad-dition to the 6.8% of the daily value for folate already mentionedpreviously in relation to its protective actions against cardiovas-cular disease, a cup of tomatoes contains 5.3% of the DV for ri-boflavin and 7.5% of the DV for chromium. Tomatoes are a greatfood loaded with a variety of vital nutrients. They also make awonderful addition to a heart-healthy and cancer-preventing diet(Lazarus and others 2004).

Despite the overwhelming evidence linking lycopene to var-ious beneficial bioactivities, a number of inconsistencies existin the epidemiological data regarding lycopene’s role in diseaseprevention.

Future DirectionsConsumers’ demand for healthy food products provides an op-

portunity to develop lycopene-rich products as new functionalfoods, as well as food-grade and pharmaceutical-grade lycopeneas new nutraceutical products. An industrial-scale, environmen-tally friendly lycopene extraction and purification procedure with



minimal loss of bioactivities is highly desirable for the food, feed,cosmetic, and pharmaceutical industries. High-quality lycopeneproducts that meet food safety regulations will offer potential ben-efits to the food industry. The current dietary recommendation toincrease the consumption of fruits and vegetables rich in antioxi-dants has generated interest in the role of lycopene in disease pre-vention. However, the evidence thus far is mainly suggestive, andthe underlying mechanisms are not clearly understood. Furtherresearch is critical to elucidate the role of lycopene and to formu-late guidelines for healthy eating and disease prevention. Moreinformation on lycopene bioavailability, however, is needed.The pharmacokinetic properties of lycopene remain particularlypoorly understood. Areas for further study include epidemiolog-ical investigations based on serum lycopene levels, bioavailabil-ity and effects of dietary factors, long-term dietary interventionstudies, metabolism and isomerization of lycopene and their bi-ological significance, interaction with other carotenoids and an-tioxidants, and mechanism of disease prevention.

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