Origin of the term lycopene

The tomato is a native fruit of the area including the southern part of North America, Central America and South America. It was in- troduced to Europe in 1540 by Hern├ín Cort├®s. The tomato goes under the official scientific name of Solanum lycopersicum. Lycopersicum (wolf peach) is the Latin expression that gave rise to the term lycopene. This is the name generally given to the tomato’s red pigment but ac- tually lycopene is also present in the watermelon, grapefruit, papaya and pink guava 1 Frenich AG, Torres ME, Vega AB, et al. Determination of ascorbic acid and carotenoids in food commodities by liquid chromatography with mass spectrometry detection. J Agric Food Chem. 2005; 53:7371-6. 2 Lugasi A, Biro L, Hovarie J, et al. Lycopene content of food and lycopene intake in two groups of the Hungarian population. Nutr Res. 2003; 23:1035-44. 3
Setiawan B, Sulaeman A, Giraud DW, Driskell JA. Carotenoid content of selected Indonesian fruits. J Food Comp Anal. 2001; 14:169-176.
.

Chemistry of lycopene

From a chemical viewpoint, lycopene is a carotenoid, an acyclic isomer of ╬▓-carotene. It is an unsaturated hydrocarbon containing 11 double conjugated bonds and two unconjugated bonds

Lycopene: summary of chemical and biological properties

The double bonds present in lycopene can undergo cis-trans isomer – isation, theoretically offering the possibility of 1056 configurations 4 Zechmeister L, Polg├ír A. Cis-trans isomerization and cis-peak effect in the a-carotene set and in some other stereoisomeric sets. J Am Chem Soc. 1944; 66: 137-144. . Due to the presence of some steric hindrances, only certain groups of double bonds can undergo geometric isomerisation. Cis-transisomerisation can be induced by light, by thermal energy and by chemical reactions. In nature, lycopene occurs in the trans isomeric form, which is the thermodynamically most stable form 5 Nguyen ML, Schwartz SJ. Lycopene: chemical and biological properties. Food Technol. 1999; 53:38-45. 6 Zechmeister L, LeRosen AL, Went FW, Pauling L. Prolycopene, a naturally occurring stereoiso- mer of lycopene. Proc Natl Acad Sci. USA 1941; 21:468-74. .

Lycopene in the human body

Lycopene present in the human body is not synthesised lo- cally but comes from the diet. Due to its lipophilic properties, lycopene occurs in the serum concentrated in the LDL and VLDL related fraction 7 Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nu- tr Rev .1998; 56:35-51. . In the serum and tissues (liver, testicles, adrenal glands, prostate and skin), lycopene is mainly present in the cisform; in some organs (pro- state and testicles) cis isomers represent more than 80% of isolatable lycopene 8 Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat- processed than from unprocessed tomato juice in humans. J Nutr 1992; 122:2161-2166. 9 Schierle J, Bretzel W, Buhler I, et al. Content and isomeric ratio of lycopene in food and hu- man plasma. Food Chem. 1997; 59:459-465. .

The tomato as the main source of lycopene in the diet

More than 80% of lycopene occurring in the human body comes from the consumption of the tomato or its by-products (sauces, juices, concentrates, etc.) 10 Canene-Adams K, Campbell JK, Zaripheh S, et al. The tomato as a functional food. J Nutr. 2005; 135:1226-30. . The lycopene content of tomato fruit depends on the variety and level of ripeness. Ripe tomatoes can contain from 30 to more than 100 mg of lycopene per kg of fresh product 11 Rescio L, Di Maio A, Cazzola P. Lycopene, photoprotection and skin care: the benefits of or- ganic quality. J Plastic Dermatol. 2010; 6:37-47 . Some studies on lycopene distri bution in tomatoes have shown that the epicarp and the pericarp are the parts richest in this carotenoid 12 DÔÇÖSouza MC, Singha S, Ingle. M. Lycopene concentration of tomato fruit can be estimated from chromaticity values. Hort Science 1992; 27:465-466. 13
Sharma SK, Le Maguer M. Lycopene in tomatoes and tomato pulp fractions. Ital J Food Sci. 1996: 2:107-113.
. A study carried out by Lucarini, et al.indicated that the daily intake of lycopene in Italy amounts to 7.4 mg 14 Lucarini M, Lanzi S, D’Evoli L, et al. Intake of vitamin A and carotenoids from the Italian population–results of an Italian total diet study. Int J Vitam Nutr Res. 2006; 76:103-9. .

Bioavailability and absorption of lycopene

Lycopene from the consumption of fresh tomatoes or tomato juice has a low bio-availability; tomato pastes and concentrates offer higher bio-availability. This is a direct consequence of processing that involves the mincing of tissues and some heat treatments that increase the ratio between the cis-transisomers 15 Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat- processed than from unprocessed tomato juice in humans. J Nutr 1992; 122:2161-2166. 16 Gartner C, Stahl W & Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997; 6:116-122. 17 Bohm V & Bitsch R. Intestinal absorption of lycopene from different matrices and interac- tions to other carotenoids, the lipid status, and the antioxidant capacity of human plasma. Eur J Nutr. 1999; 38:118-125. 18 Van het Hof KH, de Boer BCJ, Tijburg LBM, et al. Carotenoid bioavailability in humans from tomatoes processed in different ways determined from the carotenoid response in the triglyceride-rich lipoprotein fraction of plasma after a single consumption and in plasma after four days of consumption. J Nutr. 2000; 130:1189-1196. 19 Van het Hof KH, West CE, Westrade JA, Hauvast JGAJ. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000; 130:503-506. 20 Porrini M, Riso P, Testolin G. Absorption of lycopene from single or daily portions of raw and processed tomato. Br J Nutr. 1998; 80:353-361. . The bio-availability of lycopene is strongly influenced by various factors including isomeric configuration (the cisisomers are more bioavailable than the trans), physical state (level of crystallinity and size of lycopene crystals) and concomitant consumption of lipids in the diet 21 Van het Hof KH, West CE, Westrade JA, Hauvast JGAJ. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000; 130:503-506. . This is because all lycopene configurations are insoluble in water but the compound dissolves in oils as it is a non-polar compound. This is why the Mediterranean diet, using cooked tomatoes and olive oil is not only an effective source of lycopene but also promotes its absorption through the bowel20. In the stomach, transforms of lycopene are converted to cis 22
Re R, Fraser PD, Long M, et al. Isomerization of lycopene in the gastric milieu. Biochem Biophys Res Commun. 2001; 281(2):576-81.
. In the duodenum, lipid droplets containing lycopene, in contact with bile acids, form micelles that reach the small intestine 23 Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996; 10:542-51. 24 Gruenwald J, Jaenicke C, Freder J. Lycopene: the modern answer to urban wellness? Nutra Foods 2003; 2:21-35. . The passage from the intestinal lumen to the cells of the intestinal mucosa seems to be linked to a passive diffusion process, although it is unclear whether the lycopene is carried by specific proteins or migrates in lipid droplets 25 Boileau TW, Boileau AC, Erdman JW Jr. Bioavailability of all-trans and cis-isomers of ly- copene. Exp Biol Med (Maywood). 2002; 227:914-9. 26 Gugger ET, Erdman JW Jr. Intracellular beta-carotene transport in bovine liver and intes- tine is not mediated by cytosolic proteins. J Nutr. 1996; 126:1470-4. . The lycopene is then incorporated into the chylomicrons and released into the mesenteric lymphatic system, which then releases it into the bloodstream 27
Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996; 10:542-51.
.

Metabolism of lycopene

The in vivo metabolism of lycopene has been detailed in a wide-ranging review by Mein JR, et al. 28 Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for can- cer prevention. Nutr Rev. 2008; 66:667-83. . Metabolites of lycopene, known also as lycopenoids, are poly- isoprenoid compounds containing fewer than 40 carbon atoms 29
Lindshield BL, Canene-Adams K, Erdman JW Jr. Lycopenoids: are lycopene metabolites bioactive? Arch Biochem Biophys. 2007; 458:136-40.
. The latter can form by oxidation due to free radicals, to lipoxygenase activity, to phase II detoxifying enzymes or carotenoid cleavage enzymes 30 Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for can- cer prevention. Nutr Rev. 2008; 66:667-83. . The enzymatic metabolism of carotenoids is primarily catalysed by two mono-oxygenases: carotene-15,15ÔÇÖ-monoxygenases (CMO-I) and carotene-9ÔÇÖ,10ÔÇÖ-monooxygenase (CMO-II). CMO-I acts in the central portion of carotenoids such as ╬▓-carotene 31 Hessel S, Eichinger A, Isken A, et al. CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem. 2007; 282:33553-61. , while CMO-II acts in the eccentric portion of non-provitamin A carotenoids such as lycopene 32 Hu KQ, Liu C, Ernst H, et al. The biochemical characterization of ferret carotene-9′,10′- monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem. 2006; 281:19327-38. 33 Ford NA, Clinton SK, von Lintig J, et al. Loss of carotene-9′,10′-monooxygenase expression in- creases serum and tissue lycopene concentrations in lycopene-fed mice. J Nutr. 2010; 140(12):2134-8. . CMO-II is expressed in a different way in the various human tissues 34 Ford NA, Erdman JW Jr. Are lycopene metabolites metabolically active? Acta Biochim Pol. 2012; 59:1-4. (Table 1).

Products originating from CMO-II are short-chain aldehydes known as apo-lycopenals which can undergo oxidation (lycopenols) or reduction 35 Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for can- cer prevention. Nutr Rev. 2008; 66:667-83. (Figure 2). Recent studies have emphasized the importance of lycopene metabolites in determining their numerous biological activities (Figure 3). Unlike ╬▓-carotene, lycopene is not converted by the body to vitamin A and must therefore express its functions using different mechanisms from the latter 36 Stahl W, Sies H. Lycopene: A biologically important carotenoid for humans? Arch Biochem Biophys 1996; 336:1-9. , even though the similarity of the chemical structure of its metabolite, with acyclo-retinoic acid, could suggest the existence of common receptors 37 Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for can- cer prevention. Nutr Rev. 2008; 66:667-83. .

Antioxidant activity of lycopene

The energy necessary for the human body to function is derived from the oxidative metabolism of macronutrients introduced in the diet. This nevertheless produces reactive oxygen species (ROS) and reactive nitrogen species (RNS).

High reactive species levels alter normal cell function by interacting directly with macromolecules (proteins, lipids, nuclear and mito-chondrial DNA) that constitute the cell structures, or indirectly by triggering the additional production and propagation of an ever- increasing number of reactive molecules: the final result of this cascade of reactions is cell dysfunction and/or death (oxidative stress). In order to contain or diminish this oxidative attack, higher organisms have developed an antioxidant defence system made up of anti-oxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) as well as enzymes that regulate the redox state of the cell environment (glucose 6-phosphate dehydrogenase, glutathione reductase, thioredoxin reductase and gamma-glutamylcysteine syn- thase), DNA repair enzymes, proteasome degradation system protein and phase II enzymes. These defences protect the cell against the toxicity of reactive species through a variety of reactions. The main ones involve conversion to less reactive and less toxic species by means of conjugation with endogenous substrates that facili- tate excretion. When the production of reactive species greatly out- strips the compensating potential of the antioxidant barrier, damage cannot be avoided. Although lycopene possesses numerous activities useful for human health, its antioxidant activity is considered the most important in preventing chronic diseases 38 Palozza P, Catalano A, Simone R, Cittadini A. Lycopene as a guardian of redox signalling. Acta Biochim Pol. 2012; 59:21-5. . Carotenoids generally operate by intercepting the ROSs or RNSs and deactivating these molecules by energy transfer. This energy can be dissipated in the form of heat into the surrounding aqueous environ- ment or destroy the carotenoid itself. In order to be effective antioxidants, carotenoids must be present in appropriate concentrations at the specific site where the ROSs or RNSs 39 Sies H. Total antioxidant capacity: appraisal of a concept. J Nutr. 2007; 137:1493-5. are produced. Lycopene is one of the most powerful natural antioxidants due to its high number of conjugated dienes. It has been shown to display the highest scavenging capacity of all the natural carotenoids against free radicals in vitro 40
Miller NJ, Sampson J, Candeias LP, et al. Antioxidant activities of carotenes and xantho- phylls. FEBS Lett. 1996; 384:240-242.
and is twice and ten times more effective in deactivating singlet oxygen than ╬▓-carotene and ╬▒-tocopherol respectively 41
Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989; 274:532-38.
. Numerous studies in vivo have shown that tomatoes or their derivatives reduce damage to DNA 42 Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002; 227:886-93 43 Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst. 2001; 93:1872-1879. 44 Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat- processed than from unprocessed tomato juice in humans. J Nutr 1992; 122:2161-2166. , lower susceptibility to oxidative stress of lymphocytes 45 Porrini M, Riso P. Lymphocyte lycopene concentration an DNA protection from oxidative damage is increased in women after a short period of tomato consumption. J Nutr. 2000; 130:189-192. 46 Riso P, Pinder A, Santangelo A, Porrini M. Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage? Am J Clin Nutr. 1999; 69:712-718. and reduce LDL oxidation or lipid peroxidation 47 Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human di- etary intervention study. Lipids. 1998; 33:981-984. 48 Bub A, Watzl B, Abrahamse L, et al. Moderate intervention with carotenoid-rich vegetable products reduces lipid peroxidation in men. J Nutr. 2000; 130:2200-2206. . The in vivo antioxidant activity of lycopene has been subject to exten- sive review by Erdman, et al. 49 Erdman JW Jr, Ford NA, Lindshield BL. Are the health attributes of lycopene related to its antioxidant function? Arch Biochem Biophys. 2009; 483:229-35. . It was recently suggested that lycopene can directly control redox- sensitive molecular targets by regulating the expression and activity of some enzymes and modulating the activation of Antioxidant Re- sponse Elements (ARE), ROS-producing enzymes, GTPases, Mitogen- Activated Protein Kinases (MAPK) and some nuclear factors (NF-╬║B, AP-1 and Nrf2) (Figure 4) 50 Palozza P, Catalano A, Simone R, Cittadini A. Lycopene as a guardian of redox signalling. Acta Biochim Pol. 2012; 59:21-5. .

Other actions of lycopene

In addition to its antioxidant activity, lycopene also performs the following actions that are useful in the prevention (and treatment?) of certain types of cancer:

– Apoptosis: although little data is available, in vivo studies have indicated that lycopene induces apoptosis in cancer cells 51
Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002; 227:886-93
52 Kim HS, Bowen P, Chen L, et al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003; 47:40-7 53 Canene-Adams K, Lindshield BL, Wang S, et al. Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas. Cancer Res. 2007; 67:836-43. 54 Tang L, Jin T, Zeng X, Wang JS. Lycopene inhibits the growth of human androgen-indepen- dent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr. 2005; 135:287-90. 55
Liu C, Lian F, Smith DE, et al. Lycopene supplementation inhibits lung squamous metapla- sia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in ciga- rette smoke-exposed ferrets. Cancer Res. 2003; 63:3138-44.
56 Liu C, Russell RM, Wang XD. Lycopene supplementation prevents smoke-induced changes in p53, p53 phosphorylation, cell proliferation, and apoptosis in the gastric mucosa of ferrets. J Nu- tr. 2006; 136:106-11. 57 Velmurugan B, Nagini S. Combination chemoprevention of experimental gastric carcino- genesis by s-allylcysteine and lycopene: modulatory effects on glutathione redox cycle antioxi- dants. J Med Food. 2005; 8:494-501. 58 Sengupta A, Ghosh S, Das S. Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats. Eur J Cancer Prev. 2003; 12:195-200. .

– Cell proliferation: the inhibitory effects of lycopene on cell growth were demonstrated for the first time by Levy, et al. 59 Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer. 1995; 24:257-266. 1. These were subsequently confirmed on several cancerous 60 Nahum A, Hirsch K, Danilenko M, et al. Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E-cdk2 complexes. Oncogene. 2001; 20:3428-3436. 61 Salman H, Bergman M, Djaldetti M, Bessler H. Lycopene affects proliferation and apopto- sis of four malignant cell lines. Biomed Pharmacother. 2007; 61:366-369. 62 Livny O, Kaplan I, Reifen R, et al. Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J Nutr. 2002; 132:3754-3759. and non-cancerous 63 Obermuller-Jevic UC, Olano-Martin E, Corbacho AM, et al. Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr. 2003; 133:3356-3360. cell lines. It has recently shown that supplementation with lycopene reduces in vivo metastasis of experimental tumours and that this effect is due to the action on cell proliferation, tumour invasion and angiogenesis 64 Huang CS, Liao JW, Hu ML. Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. J Nutr. 2008; 138:538-543. .

– Phase II enzymes: in general, phase II enzymes increase the hydro- philicity of carcinogens and enhance their detoxification and excre- tion. In recent years, evidence has built up to indicate that the beneficial effects of lycopene may be partly due to the induction of phase II detoxifying enzymes 65 Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors. 2000; 12:5-11. . In particular, it has been shown that supplementation of the diet with lycopene significantly increases the activation of enzymes such as glutathione reductase, glutathione S-transferase and quinone reductase 66 Breinholt V, Lauridsen ST, Daneshvar B, Jakobsen J. Doseresponse effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 2000; 154:201-210. .

– Gap junctions: these channels present between cells allow the ex- change of nutrients, breakdown products and information. Each gap junction is made up of 12 protein structures called connexins (six for each cell element) of which the most greatly expressed is Cx 43. Junctions are involved in the control of cell growth through adaptive responses (differentiation, proliferation and apoptosis) 67 Trosko JE, Chang CC, Upham B, Wilson M. Epigenetic toxicology as toxicant-induced changes in intracellular signalling leading to altered gap junctional intercellular communication. Toxicol Lett. 1998; 102-103:71-78. . There is evidence to suggest that loss of expression of Cx43 is a sign of carcinogenicity 68 King TJ, Bertram JS. Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta. 2005; 1719:146-160. . Experimental studies have shown that lycopene increases Cx43 expression in some human breast cancer cell lines 69Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of hu- man breast cell line (MCF-7). Toxicol In Vitro. 2007; 21:217-23. 70
Chalabi N, Delort L, Satih S, et al. Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem. 2007; 55:877-83.
.

– Growth factors: Insulin Growth Factors (IGFs) are mitogens that play an important role in cell proliferation, differentiation and apoptosis 71 Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000; 92:1472-89. . Changes in the normal functioning of these growth factors have been implicated in the development of various tumours 72 Jerome L, Shiry L, Leyland-Jones B. Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions. Endocr Relat Cancer. 2003; 10:561-78. . It was initially observed that lycopene altered the IGF-1 axis, although a review of the literature failed to provide categorical evidence for this 73 Erdman JW Jr, Ford NA, Lindshield BL. Are the health attributes of lycopene related to its antioxidant function? Arch Biochem Biophys. 2009; 483:229-35. . This potential activity is therefore worth further study.

– Angiogenesis: see page 47 for the antiangiogenic effect of lycopene

Biological activity of lycopene metabolites

Preliminary studies indicate that lycopenoids are biologically active and can therefore reduce the risk of chronic diseases 74 Ford NA, Erdman JW Jr. Are lycopene metabolites metabolically active? Acta Biochim Pol. 2012; 59:1-4. . Investigations are therefore in progress to clarify these aspects.

References   [ + ]

1. Frenich AG, Torres ME, Vega AB, et al. Determination of ascorbic acid and carotenoids in food commodities by liquid chromatography with mass spectrometry detection. J Agric Food Chem. 2005; 53:7371-6.
2. Lugasi A, Biro L, Hovarie J, et al. Lycopene content of food and lycopene intake in two groups of the Hungarian population. Nutr Res. 2003; 23:1035-44.
3.
Setiawan B, Sulaeman A, Giraud DW, Driskell JA. Carotenoid content of selected Indonesian fruits. J Food Comp Anal. 2001; 14:169-176.
4. Zechmeister L, Polgár A. Cis-trans isomerization and cis-peak effect in the a-carotene set and in some other stereoisomeric sets. J Am Chem Soc. 1944; 66: 137-144.
5. Nguyen ML, Schwartz SJ. Lycopene: chemical and biological properties. Food Technol. 1999; 53:38-45.
6. Zechmeister L, LeRosen AL, Went FW, Pauling L. Prolycopene, a naturally occurring stereoiso- mer of lycopene. Proc Natl Acad Sci. USA 1941; 21:468-74.
7. Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nu- tr Rev .1998; 56:35-51.
8, 15. Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat- processed than from unprocessed tomato juice in humans. J Nutr 1992; 122:2161-2166.
9. Schierle J, Bretzel W, Buhler I, et al. Content and isomeric ratio of lycopene in food and hu- man plasma. Food Chem. 1997; 59:459-465.
10. Canene-Adams K, Campbell JK, Zaripheh S, et al. The tomato as a functional food. J Nutr. 2005; 135:1226-30.
11. Rescio L, Di Maio A, Cazzola P. Lycopene, photoprotection and skin care: the benefits of or- ganic quality. J Plastic Dermatol. 2010; 6:37-47
12. DÔÇÖSouza MC, Singha S, Ingle. M. Lycopene concentration of tomato fruit can be estimated from chromaticity values. Hort Science 1992; 27:465-466.
13.
Sharma SK, Le Maguer M. Lycopene in tomatoes and tomato pulp fractions. Ital J Food Sci. 1996: 2:107-113.
14. Lucarini M, Lanzi S, D’Evoli L, et al. Intake of vitamin A and carotenoids from the Italian population–results of an Italian total diet study. Int J Vitam Nutr Res. 2006; 76:103-9.
16. Gartner C, Stahl W & Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997; 6:116-122.
17. Bohm V & Bitsch R. Intestinal absorption of lycopene from different matrices and interac- tions to other carotenoids, the lipid status, and the antioxidant capacity of human plasma. Eur J Nutr. 1999; 38:118-125.
18. Van het Hof KH, de Boer BCJ, Tijburg LBM, et al. Carotenoid bioavailability in humans from tomatoes processed in different ways determined from the carotenoid response in the triglyceride-rich lipoprotein fraction of plasma after a single consumption and in plasma after four days of consumption. J Nutr. 2000; 130:1189-1196.
19, 21. Van het Hof KH, West CE, Westrade JA, Hauvast JGAJ. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000; 130:503-506.
20. Porrini M, Riso P, Testolin G. Absorption of lycopene from single or daily portions of raw and processed tomato. Br J Nutr. 1998; 80:353-361.
22.
Re R, Fraser PD, Long M, et al. Isomerization of lycopene in the gastric milieu. Biochem Biophys Res Commun. 2001; 281(2):576-81.
23. Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996; 10:542-51.
24. Gruenwald J, Jaenicke C, Freder J. Lycopene: the modern answer to urban wellness? Nutra Foods 2003; 2:21-35.
25. Boileau TW, Boileau AC, Erdman JW Jr. Bioavailability of all-trans and cis-isomers of ly- copene. Exp Biol Med (Maywood). 2002; 227:914-9.
26. Gugger ET, Erdman JW Jr. Intracellular beta-carotene transport in bovine liver and intes- tine is not mediated by cytosolic proteins. J Nutr. 1996; 126:1470-4.
27.
Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996; 10:542-51.
28, 30, 35, 37. Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for can- cer prevention. Nutr Rev. 2008; 66:667-83.
29.
Lindshield BL, Canene-Adams K, Erdman JW Jr. Lycopenoids: are lycopene metabolites bioactive? Arch Biochem Biophys. 2007; 458:136-40.
31. Hessel S, Eichinger A, Isken A, et al. CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem. 2007; 282:33553-61.
32. Hu KQ, Liu C, Ernst H, et al. The biochemical characterization of ferret carotene-9′,10′- monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem. 2006; 281:19327-38.
33. Ford NA, Clinton SK, von Lintig J, et al. Loss of carotene-9′,10′-monooxygenase expression in- creases serum and tissue lycopene concentrations in lycopene-fed mice. J Nutr. 2010; 140(12):2134-8.
34, 74. Ford NA, Erdman JW Jr. Are lycopene metabolites metabolically active? Acta Biochim Pol. 2012; 59:1-4.
36. Stahl W, Sies H. Lycopene: A biologically important carotenoid for humans? Arch Biochem Biophys 1996; 336:1-9.
38, 50. Palozza P, Catalano A, Simone R, Cittadini A. Lycopene as a guardian of redox signalling. Acta Biochim Pol. 2012; 59:21-5.
39. Sies H. Total antioxidant capacity: appraisal of a concept. J Nutr. 2007; 137:1493-5.
40.
Miller NJ, Sampson J, Candeias LP, et al. Antioxidant activities of carotenes and xantho- phylls. FEBS Lett. 1996; 384:240-242.
41.
Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989; 274:532-38.
42. Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002; 227:886-93
43. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst. 2001; 93:1872-1879.
44. Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat- processed than from unprocessed tomato juice in humans. J Nutr 1992; 122:2161-2166.
45. Porrini M, Riso P. Lymphocyte lycopene concentration an DNA protection from oxidative damage is increased in women after a short period of tomato consumption. J Nutr. 2000; 130:189-192.
46. Riso P, Pinder A, Santangelo A, Porrini M. Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage? Am J Clin Nutr. 1999; 69:712-718.
47. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human di- etary intervention study. Lipids. 1998; 33:981-984.
48. Bub A, Watzl B, Abrahamse L, et al. Moderate intervention with carotenoid-rich vegetable products reduces lipid peroxidation in men. J Nutr. 2000; 130:2200-2206.
49. Erdman JW Jr, Ford NA, Lindshield BL. Are the health attributes of lycopene related to its antioxidant function? Arch Biochem Biophys. 2009; 483:229-35.
51.
Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002; 227:886-93
52. Kim HS, Bowen P, Chen L, et al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003; 47:40-7
53. Canene-Adams K, Lindshield BL, Wang S, et al. Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas. Cancer Res. 2007; 67:836-43.
54. Tang L, Jin T, Zeng X, Wang JS. Lycopene inhibits the growth of human androgen-indepen- dent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr. 2005; 135:287-90.
55.
Liu C, Lian F, Smith DE, et al. Lycopene supplementation inhibits lung squamous metapla- sia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in ciga- rette smoke-exposed ferrets. Cancer Res. 2003; 63:3138-44.
56. Liu C, Russell RM, Wang XD. Lycopene supplementation prevents smoke-induced changes in p53, p53 phosphorylation, cell proliferation, and apoptosis in the gastric mucosa of ferrets. J Nu- tr. 2006; 136:106-11.
57. Velmurugan B, Nagini S. Combination chemoprevention of experimental gastric carcino- genesis by s-allylcysteine and lycopene: modulatory effects on glutathione redox cycle antioxi- dants. J Med Food. 2005; 8:494-501.
58. Sengupta A, Ghosh S, Das S. Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats. Eur J Cancer Prev. 2003; 12:195-200.
59. Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer. 1995; 24:257-266.
60. Nahum A, Hirsch K, Danilenko M, et al. Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E-cdk2 complexes. Oncogene. 2001; 20:3428-3436.
61. Salman H, Bergman M, Djaldetti M, Bessler H. Lycopene affects proliferation and apopto- sis of four malignant cell lines. Biomed Pharmacother. 2007; 61:366-369.
62. Livny O, Kaplan I, Reifen R, et al. Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J Nutr. 2002; 132:3754-3759.
63. Obermuller-Jevic UC, Olano-Martin E, Corbacho AM, et al. Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr. 2003; 133:3356-3360.
64. Huang CS, Liao JW, Hu ML. Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. J Nutr. 2008; 138:538-543.
65. Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors. 2000; 12:5-11.
66. Breinholt V, Lauridsen ST, Daneshvar B, Jakobsen J. Doseresponse effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 2000; 154:201-210.
67. Trosko JE, Chang CC, Upham B, Wilson M. Epigenetic toxicology as toxicant-induced changes in intracellular signalling leading to altered gap junctional intercellular communication. Toxicol Lett. 1998; 102-103:71-78.
68. King TJ, Bertram JS. Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta. 2005; 1719:146-160.
69. Fornelli F, Leone A, Verdesca I, et al. The influence of lycopene on the proliferation of hu- man breast cell line (MCF-7). Toxicol In Vitro. 2007; 21:217-23.
70.
Chalabi N, Delort L, Satih S, et al. Immunohistochemical expression of RARalpha, RARbeta, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem. 2007; 55:877-83.
71. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000; 92:1472-89.
72. Jerome L, Shiry L, Leyland-Jones B. Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions. Endocr Relat Cancer. 2003; 10:561-78.
73. Erdman JW Jr, Ford NA, Lindshield BL. Are the health attributes of lycopene related to its antioxidant function? Arch Biochem Biophys. 2009; 483:229-35.