HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, A. V. Articles by Agarwal, S. Search for Related Content PubMed PubMed Citation Articles by Rao, A. V. Articles by Agarwal, S.

Role of Antioxidant Lycopene in Cancer and Heart Disease

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, Ontario CANADA

Address reprint requests to: Dr. A. V. Rao, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, Ontario M5S 3E2, CANADA. E-mail: v.rao{at}utoronto.ca.

	ABSTRACT

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Lycopene, a carotenoid without provitamin-A activity, is present in many fruits and vegetables; however, tomatoes and processed tomato products constitute the major source of lycopene in North American diet. Among the carotenoids, lycopene is a major component found in the serum and other tissues. Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases such as cancer and cardiovascular diseases in several recent studies. Serum and tissue lycopene levels have also been inversely related with the chronic disease risk. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial properties, evidence is accumulating to suggest other mechanisms such as modulation of intercellular gap junction communication, hormonal and immune system and metabolic pathways may also be involved. This review summarizes the background information about lycopene and presents the most current knowledge with respect to its role in human health and disease.

Key words: lycopene, carotenoids, oxidative stress, antioxidant, chronic diseases

Key teaching points:

• Oxidative stress is causally related to the incidence of chronic diseases such as cancer and heart disease.

• Lycopene may be a key component responsible for the protective effects of fruits and vegetables.

• Tomatoes and tomato products are the main dietary sources of lycopene.

• Lycopene is a major carotenoid of plasma and other body tissue.

• Dietary intake and/or serum levels of lycopene have been reported to be inversely related to the risk of cancer and heart diseases.

• Recommended daily intake of lycopene is 35 mg which can be obtained by ingesting two glasses of tomato juice or through a combination of tomato products.

	BIOCHEMISTRY AND PHYSIOLOGY

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Lycopene is a natural pigment synthesized by plants and microorganisms but not by animals. It is a carotenoid, an acyclic isomer of ß-carotene, and has no vitamin A activity [1,2]. It is a highly unsaturated, straight chain hydrocarbon containing 11 conjugated and two non-conjugated double bonds. Recent interest in lycopene has focused on its antioxidant properties [1–3]. However, other mechanisms such as modulation of intercellular gap junction communication [4,5], hormonal and immune system [6–8] and metabolic pathways [9,10] are also beginning to be investigated.

As a polyene it undergoes cis-trans isomerization induced by light, thermal energy or chemical reactions [3,11]. Lycopene from natural plant sources exists predominantly in trans configuration, the most thermodynamically stable form [3,11]. In human plasma, lycopene is an isomeric mixture containing 50% of the total lycopene as cis isomers. All trans, 5-cis, 9-cis, 13-cis and 15-cis are most commonly identified isomeric forms of lycopene [12]. The biological significance of these isomers of lycopene is unclear.

Lycopene, ingested in its natural trans form found in tomatoes, is poorly absorbed. Recent studies have shown that heat processing of tomatoes and tomato products induces isomerization of lycopene to the cis form which in turn increases its bioavailability [13]. However, there is some indication that isomerization reactions may be taking place in the body. High concentration of cis isomers were also observed in human serum and prostate tissue [12], suggesting that tissue isomerases might be involved in in vivo isomerization of lycopene from all trans to cis form.

In a recently completed study [14] we demonstrated that serum and prostate levels of lycopene in prostate cancer patients were significantly lower than their age matched controls. It is hypothesized that prostate cancer patients perhaps lack the ability to isomerize dietary lycopene and therefore do not absorb it efficiently.

	AVAILABILITY IN DIFFERENT FOOD PRODUCTS

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Lycopene is mainly available from a very limited list of fruits and vegetables, in contrast to other dietary carotenoids. Red fruits and vegetables, including tomatoes, watermelons, pink-grapefruits, apricots and pink-guavas, are the most common sources of lycopene [1,3]. Tomatoes and processed tomato products such as juice, ketchup, paste, sauce and soup all are good sources of lycopene and may account for over 85% of dietary lycopene in the North American diet. The lycopene content of tomatoes varies with the variety and increases with fruit ripening.

In a recent study [15], we assessed the average daily dietary lycopene intake levels by administering a food frequency questionnaire and estimated it to be 25 mg/day, with processed tomato products accounting for 50% of the total intake. Based on these findings it was concluded that the recommended daily intake of lycopene of 35 mg was not being met. Lycopene from processed tomato products appears to be more bioavailable than from raw tomatoes [13]. Comparative bioavailabilities of lycopene from different tomato products such as paste, juice, ketchup, sauce and soup are not known. However, lycopene from tomato paste was shown to be more bioavailable than from fresh tomatoes [16]. Release of lycopene from the food matrix due to processing, presence of dietary lipids and heat-induced isomerization from all trans to cis conformation enhance lycopene bioavailability [1,17]. It is however not clear if cis-isomers are biologically more effective than trans-isomers. Bioavailability of lycopene is also affected by the dose and presence of other carotenoids such as ß-carotene [18].

	CELLULAR AND MOLECULAR STUDIES ON THE POTENTIAL PREVENTIVE ACTION IN HEART DISEASE AND CARCINOGENESIS

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Reactive oxygen species (ROS) and the related oxidative damage have been implicated in the pathogenesis of various human chronic diseases [19–22]. Lycopene is one of the most potent antioxidants [23] and has been suggested to prevent carcinogenesis and atherogenesis by protecting critical biomolecules including lipids, low-density lipoproteins (LDL), proteins and DNA [24–26]. Several studies have indicated that lycopene is an effective antioxidant and free radical scavenger. Lycopene, because of its high number of conjugated double bonds, exhibits higher singlet oxygen quenching ability compared to ß-carotene or -tocopherol [27]. In in vitro systems, lycopene was found to inactivate hydrogen peroxide and nitrogen dioxide [28,29]. Using pulse radiolysis techniques, Mortesen et al. [30] demonstrated its ability to scavenge nitrogen dioxide (NO₂^·), thiyl (RS^·) and sulphonyl (RSO₂^·) radicals. Lycopene is highly lipophilic and is most commonly located within cell membranes and other lipid components. It is therefore expected that in the lipophylic environment lycopene will have maximum ROS scavenging effects. Lycopene was shown to be the most effective antioxidant in protecting the 2,2'-azo-bis(2,4-dimethylvaleronitrile) (AMVN)-induced lipid peroxidation of the liposomal membrane [31]. Oxidative modification of LDL is hypothesized to be the key step in the atherogenic process, and LDL associated antioxidants provide protection against this oxidation [32]. In vitro lycopene and other carotenoids are able to inhibit oxidation of LDL [33]. Lycopene was also found to protect lymphocytes against NO₂^·-induced membrane damage and cell death twice as efficiently as ß-carotene [28,34]. In vivo antioxidant effects of lycopene and its interaction with the host and other dietary antioxidants are now being investigated.

A number of studies have used tissue culture and in vitro systems to demonstrate potential disease preventive action of lycopene and provided a mechanistic hypothesis. Levy et al. [6] showed that lycopene inhibited the growth of human endometrial, mammary and lung cancer cells grown in cultures and was more effective than - or ß-carotene. Lycopene along with vitamin D3 synergistically inhibited cell cycle progression and induced differentiation of the HL60 promyelocytic leukemia cell line [35]. In mouse embryo fibroblast cells, lycopene enrichment upregulated gap-junction-communication by enhancing the expression of the connexin43 gene, which encodes a major gap junction protein, and thereby acted as an anticarcinogenic agent [4,5]. Lycopene was also shown to protect against microcystinCR-induced mouse hepatocarcinoma by suppressing the phosphorylation of regulatory proteins and arresting cells in the G0/G1 phase of the cell cycle [36]. Preliminary in vitro evidence indicates that lycopene reduces cellular proliferation induced by IGF-1 in various cancer cell lines [6]. In a recent investigation, lycopene, together with -tocopherol at physiological concentrations, synergistically inhibited cell proliferation of an androgen insensitive prostate carcinoma cell line [37]. In the J774A.1 macrophage cell line, lycopene was shown to act as a hypocholesterolemic agent by inhibiting the HMG-CoA reductase pathway [10].

	RELEVANT ANIMAL DATA

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Lycopene may play an important protective role in several human cancers. Animal models have been used to measure lycopene’s absorption and tissue distribution. Jain et al. [38] have recently demonstrated that 10 ppm dietary lycopene in rat diet was absorbed and distributed to various tissues. Liver, spleen and prostate showed the highest levels of lycopene, whereas brain had the lowest level. The varying levels of lycopene in different tissues suggest its selective uptake involving tissue-specific mechanism(s) [38]. Use of animal models to investigate in vivo biochemical functions of lycopene has allowed undertaking studies under well-defined, controlled environmental conditions where the confounding variables are minimum. Although several animal models of experimental cancer are available, very little is known about the absorption, metabolism and distribution of dietary lycopene and the possible mechanism of its effects on carcinogenesis. As early as 1959, dietary lycopene or intraperitonial injections of lycopene were demonstrated to provide protection against ionizing radiation, resistance towards bacterial infections and inhibition of ascites-producing tumors in mice [39,40].

In rats, growth and development of C-6 glioma cell xenographs were inhibited by intraperitonial injections of lycopene [41]. Growth-inhibitory effects were more pronounced when lycopene was given before the glioma cell inoculation. Chronic dietary intake of lycopene markedly delayed the onset and reduced growth and development of spontaneous mammary tumors in a mouse strain with high incidence [7]. This effect was associated with reduced activity of mammary gland thymidylate synthetase and lowered levels of serum free fatty acids and prolactin, a hormone known to be involved in breast cancer development that stimulates cell division. Lycopene was also shown to enhance the immune response by increasing helper T cells and normalizing intrathymic T cell differentiation caused by tumorigenesis in mice [8]. Lycopene in small doses reduced the N-methylnitrosourea (MNU)-induced development of aberrant crypt foci (ACF) in the colon of Sprague-Dawley rats [42]. In a dimethylbenzanthracene (DMBA)-induced mammary tumor model of rats, intraperitoneal injections of lycopene-enriched tomato oleoresin, but not of ß-carotene, suppressed tumor growth as quantified by size and tumor numbers [43].

Diethylnitrosamine (DEN)-induced liver preneoplastic foci in rats were significantly reduced by dietary lycopene and not by any other carotenoid tested [9]. It was hypothesized that lycopene provided protection through its modulating effect on the liver enzymes activating diethylnitrosamine, cytochrome P-450 2E1, and not through an antioxidative mechanism [9]. Ingestion of tomato juice inhibited the development of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced development of urinary bladder transitional cell carcinomas in male Fischer 344 rats [44]. Recent investigations in our laboratory indicated that dietary lycopene (10 ppm) significantly reduced lipid and protein oxidation and demonstrated an apparent protective effect against azoxymethane (AOM)-induced colonic preneoplastic lesions [38]. Dietary lycopene in the form of vegetable juice was also found to be protective against AOM-induced aberrant crypt foci in the rat colon model [45].

Dietary lycopene dissolved in drinking water at a 50 ppm dose significantly decreased diethylnitrosamine (DEH)-, methylnitrosourea (MNU)- and dimethylhydrazine (DMD)-induced lung adenomas along with carcinomas in male mice [46]. The protective effects of lycopene against lung cancer were, however, not observed in female mice. Similarly, dietary lycopene did not alter colon or kidney tumors in the same study [46]. In another study, treatment with dietary lycopene had no effect on tobacco-smoke carcinogens benzo[a]pyrene and 4-[methyl]nitrosamino]-1-[3-pyridyl]-1-butanone induced-lung tumor multiplicity in A/J mice [47]. Lack of protection against benzopyrene-induced lung tumors was probably due to the lack of involvement of DNA oxidation in this model. Lycopene also had no effects on 2-nitropropane-induced hepatocarcinogenesis or dimethylhydrazine (DMH)-induced colon carcinogenesis in mice, as indicated by proliferation of colonic crypt epithelial cells as measured by BrdU incorporation assay [48]. Similarly, aflatoxin B1-induced liver preneoplastic foci in the rat were not affected by dietary lycopene, whereas ß-carotene provided significant protection [49].

	IMPORTANT CLINICAL STUDIES

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
The interest in lycopene and its potential protective role in prevention of chronic diseases stems largely from epidemiological observations on normal and at-risk populations. The present knowledge largely relies on the data obtained from dietary estimates or plasma values in relation to chronic diseases. Epidemiological investigations to study the role of lycopene in relation to chronic diseases has focused primarily on cancers. The Mediterranean diet, which is rich in fruits and vegetables, including tomatoes, has been suggested to be responsible for the lower cancer incidences in that region [50]. Dietary intake of tomatoes and tomato products has been found to be associated with a lower risk of a variety of cancers in a number of epidemiological studies [51]. In a prospective cohort study, Colditz et al. [52] investigated the frequency of intake of different types of vegetables and cancer deaths in 1271 elderly persons from Massachusetts. High intake of tomatoes was linked to a 50% reduction in mortality from cancers at all sites. Carrots and other carotenoid-rich vegetables had no effect [52].

The most impressive results came from U S Health Professionals Follow-up Study evaluating the intake of various carotenoids and retinol, from a food frequency questionnaire, in relation to risk of prostate cancer [53]. The estimated intake of lycopene from various tomato products, and not any other carotenoid, was inversely related to the risk of prostate cancer. A risk reduction of almost 35% was observed for a consumption frequency of 10 or more servings of tomato products per week, and the protective effects were even stronger for more advanced or aggressive prostate cancer [53]. Similarly serum and tissue levels of lycopene were inversely associated with prostate cancer risk in recent case-control and cohort studies [14,54]. It is noteworthy that no significant association with other major carotenoids including ß-carotene was observed in these studies [14,54].

High intake of tomatoes was consistently associated with reduced risk of digestive tract (especially stomach, colon and rectal) cancers in a case control study from Italy, where cases were patients with histologically confirmed cancers of oral cavity, pharynx, esophagus, stomach, colon and rectum and controls were patients with unrelated conditions [55]. Similarly, an inverse association between lycopene (estimated intakes or serum levels) and breast cancer risk was reported by some investigators in epidemiological investigations. However, these observations were not confirmed by other investigators [56–58]. In a recent case-control study from the Breast Cancer Serum Bank in Columbia, Missouri, only serum lycopene and none of the other antioxidants showed a significant inverse relationship with breast cancer risk [59]. Dietary intake of lycopene as well as serum lycopene levels showed an inverse association with the risk of cervical intraepithelial neoplasia in another case-control study [60]. In a cohort study, serum lycopene levels were found to be inversely related to the risk of bladder cancer [61]. It appears that cancer risk is inversely associated with lycopene status, which can be improved by dietary sources rich in this carotenoid as well as through supplements.

Giovannucci [51] recently reviewed 72 epidemiological studies including ecological, case-control, dietary studies and blood specime-based investigations on tomatoes, tomato-based products, lycopene and cancer. A significant number of studies analyzed demonstrated an inverse relationship between intakes of tomatoes or plasma lycopene levels and cancer. The strongest associations were observed for cancers of the prostate, lung and stomach. However, for cancers of pancreas, colon and rectum, esophagus, oral mucosa, breast and cervix the associations were only suggestive. These results were consistent across numerous diverse populations and with the use of several different study designs. None of the studies analyzed indicated increased risk of cancer [51].

Oxidation of LDL which carries cholesterol into the blood stream has been hypothesized to play an important role in the causation of atherosclerosis, the underlying disorder leading to heart attack and ischemic strokes [21,62]. Antioxidant nutrients are believed to slow the progression of atherosclerosis because of their ability to inhibit damaging oxidative processes [32,62,63]. Several epidemiological studies have provided evidence for the protective effect of vitamin E, which has been ascribed to its antioxidant properties [63–66]. However many dietary intervention trials involving -tocopherol or ß-carotene have yielded inconclusive results. Similar studies have not been performed with lycopene.

A recent multicenter case-control study (EURAMIC) evaluated the relationship between adipose tissue antioxidant status (- and ß-carotene and lycopene) and acute myocardial infarction [67]. Subjects were recruited from 10 European countries to maximize the variability in exposure within the study. After adjusting for a range of dietary variables, only lycopene, and not ß-carotene, levels were found to be protective [67]. The protective potential of lycopene was maximal among individuals with highest polyunsaturated fat stores, supporting the antioxidant theory [67]. Similarly lower blood lycopene levels were also found to be associated with increased risk and mortality from coronary heart disease in a concomitant cross-sectional study comparing Lithuanian and Swedish populations showing diverging mortality rates from coronary heart disease [68]. Limitations of the epidemiological studies undertaken to date include heterogeneous population, levels of serum carotenoids, duration of the study and biomarkers of the disease. Further studies should address these study variables to provide a more precise role of lycopene in disease prevention.

Although there is compelling epidemiological evidence in support of the role of lycopene in cancer and heart disease prevention, it only provides suggestive evidence rather than experimental proof. To date a very limited number of human intervention trials have been performed investigating the effectiveness of lycopene intake on lowering cancer and heart disease risk. Oxidative damage to lipids, proteins and DNA has been suggested to be involved in the causation and progression of cancer and heart disease [19,22]. A 50% loss of serum lycopene with an 25% increase in lipid oxidation (TBARS) was observed in human subjects ingesting a lycopene-free diet for two weeks [69]. Consumption of vegetable juices and tomato juice containing lycopene has been shown to reduce DNA strand breaks in healthy subjects [26]. Studies involving healthy human subjects in our laboratory indicated that lycopene from traditional tomato products is absorbed readily, increases serum levels and lowers oxidative damage to lipids, lipoproteins, proteins and DNA [24,25]. The level of consumption of tomato products used in this study was one to two servings/day (126 g spaghetti sauce or 500 mL tomato juice per day); that was easily achievable and in keeping with the current dietary recommendations pertaining to healthy eating. There are suggestions that tomato extract supplementation in the form of capsules lowered the PSA levels in prostate cancer patients [70]. In a small clinical trial involving six male subjects, dietary supplementation of lycopene (60 mg/d for three months) resulted in 14% reduction of plasma LDL levels and thus acted as a moderate hypocholesterolemic agent [10].

	SUMMARY OF AVAILABLE INFORMATION

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 
Lycopene is a naturally present carotenoid in tomatoes and other fruits and vegetables. Unlike ß-carotene, it does not have provitamin A activity. It is one of the most potent antioxidants among the dietary carotenoids. It is readily absorbed from different food sources, distributes to different tissues and maintains its antioxidant properties in the body. It is suggested to have anti-cell-proliferative, anticarcinogenic and antiatherogenic activities. Epidemiological and a small number of animal and experimental studies have provided evidence in support for its protective role in heart disease and cancer. Recent meta-analysis of the epidemiological literature indicated that higher intake or serum levels of lycopene are related to reduced risk for several human cancers. Although antioxidant properties of lycopene are thought to be responsible primarily for its biological effects, other mechanisms are also being identified. However, several questions, such as absorption and utilization of lycopene (alone or in combination with other antioxidants) in patients with chronic diseases, isomerization and metabolism of lycopene, biological significance of different isomers and metabolites of lycopene and the fate of lycopene in tumor cells, are still unanswered. More mechanistic studies, as well as controlled clinical intervention trials involving healthy subjects, subjects at high risk for cancer and heart disease and patients with chronic diseases, are needed to understand fully its health-promoting effects and establish clear dietary guidelines.

	FOOTNOTES

 
This is the second paper in a series on antioxidants edited by Sudhir Dutta, MD, FACN.

Received August 2, 1999. Accepted July 31, 2000.

	REFERENCES

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENT FOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA IMPORTANT CLINICAL STUDIES SUMMARY OF AVAILABLE INFORMATION REFERENCES

 

1. Rao AV, Agarwal S: Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr Res 19: 305–323, 1999.
2. Stahl W, Sies H: Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 336: 1–9, 1996.[Medline]
3. Nguyen ML, Schwartz SJ: Lycopene: chemical and biological properties. Food Tech 53: 38–45, 1999.
4. Zhang L-X, Cooney RV, Bertram JS: Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 12: 2109–2114, 1991.[Abstract/Free Full Text]
5. Zhang L-X, Cooney RV, Bertram JS: Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res 52: 5707–5712, 1992.[Abstract/Free Full Text]
6. Levy J, Bosin E, Feldmen B, Giat Y, Miinster A, Danilenko M, Sharoni Y: Lycopene is a more potent inhibitor of human cancer cell proliferation than either -carotene or ß-carotene. Nutr Cancer 24: 257–266, 1995.[Medline]
7. Nagasawa H, Mitamura T, Sakamoto S, Yamamoto K: Effects of lycopene on spontaneous mammary tumour development in SHN virgin mice. Anticancer Research 15: 1173–1178, 1995.[Medline]
8. Kobayashi T, Iijima K, Mitamura T, Toriizuka K, Cyong JC, Nagasawa H: Effects of lycopene, a carotenoid, on intrathymic T cell differentian and peripheral CD4/CD8 ratio in a high mammary tumor strain of SHN retired mice. Anti-Cancer Drugs 7: 195–198, 1996.[Medline]
9. Astrog P, Gradelet S, Berges R, Suschetet M: Dietary lycopene decreases initiation of liver preneoplastic foci by diethylnitrosamine in rat. Nutr Cancer 29: 60–68, 1997.[Medline]
10. Fuhramn B, Elis A, Aviram M: Hypocholesterolemic effect of lycopene and ß-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophage. Biochem Biophys Res Commun 233: 658–662, 1997.[Medline]
11. Zechmeister L, LeRosen AL, Went FW, Pauling L: Prolycopene, a naturally occuring sterioisomer of lycopene. Proc Natl Acad Sci USA 21: 468–474, 1941.
12. Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG, Williams AW, Moore BJ, Erdman JW: Cis-trans lycopene isomers, carotenoids and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev 5: 823–833, 1996.[Abstract]
13. 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 122: 2161–2166, 1992.
14. Rao AV, Fleshner N, Agarwal S: Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case control study. Nutr Cancer 33: 159–164, 1999.[Medline]
15. Rao AV, Waseem Z, Agarwal S: Lycopene contents of tomatoes and tomato products and their contribution to dietary lycopene. Food Res Intl, in press, 1999.
16. Gärtner C, Stahl W, Sies H: Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr 66: 116–122, 1997.[Abstract/Free Full Text]
17. Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 56: 35–51, 1998.[Medline]
18. Johnson EJ, Qin J, Krinsky NI, Russell RM: Ingestion by men of a combined dose of ß-carotene and lycopene does not affect the absorption of ß-carotene but improves that of lycopene. J Nutr 127: 1833–1837, 1997.[Abstract/Free Full Text]
19. Pincemail J: Free radicals and antioxidants in human disease. In Favier AE, Cadet J, Kalyanaraman B, Fontecave M, Pierre J-L (eds): "Analysis of Free Radicals in Biological Systems." Basel, Switzerland: Birkhäuser Verlag, pp 83–98, 1995.
20. Ames BN, Gold LS, Willet WC: Causes and prevention of cancer. Proc Natl Acad Sci USA 92: 5258–5265, 1995.[Abstract/Free Full Text]
21. Witztum JL: The oxidation hypothesis of atherosclerosis. Lancet 344: 793–795, 1994.[Medline]
22. Halliwell B: Free radicals, antioxidants and human disease: curiosity, cause or consequence? Lancet 344: 721–724, 1994.[Medline]
23. Miller NJ, Sampson J, Candeias LP, Bramley PM, Rice-Evans CA: Antioxidant activities of carotenes and xanthophylls. FEBS Lett 384: 240–246, 1996.[Medline]
24. Agarwal S, Rao AV: Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 33: 981–984, 1998.[Medline]
25. Rao AV, Agarwal S: Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in the prevention of cancer. Nutr Cancer 31: 199–203, 1998.[Medline]
26. Pool-Zobel BL, Bub A, Muller H, Wollowski I, Rechkemmer G: Consumption of vegetables reduces genetic damage in humans: first result of a human intervention trial with carotenoid-rich foods. Carcinogenesis 18: 1847–1850, 1997.[Abstract/Free Full Text]
27. DiMascio P, Kaiser S, Sies H: Lycopene as the most effective biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 274: 532–538, 1989.[Medline]
28. Bohm F, Tinkler JH, Truscott TG: Carotenoids protect against cell membrane damage by the nitrogen dioxide radical. Nature Med 1: 98–99, 1995.[Medline]
29. Lu Y, Etoh H, Watanabe N: A new carotenoid, hydrogen peroxide oxidation products from lycopene. Biosci Biotech Biochem 59: 2153–2155, 1995.
30. Mortensen A, Skibsted LH: Relative stability of carotenoid radical cations and homologue tocopheroxyl radicals. A real time kinetic study of antioxidant hierarchy. FEBS Lett 417: 261–266, 1997.[Medline]
31. Stahl W, Junghans A, deBoer B, Driomina ES, Briviba K, Sies H: Carotenoid mixtures protect multilamellar liposomes against oxidative damage: synergistic effects of lycopene and lutein. FEBS Lett 427: 305–308, 1998.[Medline]
32. Parthasarathy S: Mechanism by which dietary antioxidants may prevent cardiovascular diseases. J Med Food 1: 45–51, 1998.
33. Esterbauer H, Gebicki J, Puhl H, Jurgens G: The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 13: 341–390, 1992.[Medline]
34. Tinkler JH, Bohm F, Schalch W, Truscott TG: Dietary carotenoids protect human cells from damage. J Photochem Photobiol 26: 283–285, 1994.
35. Amir H, Karas M, Giat J, Danilenko M, Levy R, Yermiahu T, Levy J, Sharoni Y: Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 33: 105–112, 1999.[Medline]
36. Matsushima NR, Shidoji Y, Nishiwaki S, Yamada T, Moriwaki H, Muto Y: Suppression by carotenoids of microcystin-induced morphological changes in mouse hepatocytes. Lipids 30: 1029–1034, 1995.[Medline]
37. Pastori M, Pfander H, Boscoboinik D, Azzi A: Lycopene in association with -tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun 250: 582–585, 1998.[Medline]
38. Jain CK, Agarwal S, Rao AV: The effect of dietary lycopene on bioavailability, tissue distribution, in-vivo antioxidant properties and colonic preneoplasia in rats. Nutr Res 19: 1383–1391, 1999.
39. Forssberg A, Lingen C, Ernster L, Lindenberg O: Modification of x-irradiation syndrome by lycopene. Exp Cell Res 16: 7–14, 1959.[Medline]
40. Lingen C, Ernster L, Lindenberg O: The promoting effects of lycopene on the non-specific resistance of animals. Exp Cell Res 16: 384–393, 1959.
41. Wang CJ, Chou MY, Lin JK: Inhibition of growth and development of the transplantable C-6 glioma cells inoculated in rats by retinoids and carotenoids. Cancer Lett 48: 135–142, 1989.[Medline]
42. Narisawa T, Fukaura Y, Hasebe M, Nomura S, Oshima S, Sakamoto H, Inakuma T, Ishiguro Y, Takayasu J, Nishino H: Prevention of N-methylnitrosourea-induced colon carcinogenesis in F344 rats by lycopene. Jpn J Cancer Res 89: 1003–1008, 1998.[Medline]
43. Sharoni Y, Giron E, Rise M, Levy J: Effects of lycopene-enriched tomato oleoresin on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. Cancer Detect Prev 21: 118–123, 1997.[Medline]
44. Okajima E, Tsutsumi M, Ozono S, Akai H, Denda A, Nishino H, Oshima S, Sakamoto H, Konishi Y: Inhibitory effect of tomato juice on rat urinary bladder carcinogenesis after N-butyl-N-(4hydroxybutyl)nitrosamine initiation. Jpn J Cancer Res 89: 22–26, 1998.[Medline]
45. Arimochi H, Kataoka K, Kuwahara T, Nakayama H, Misawa N, Ohnishi Y: Effects of ß-glucuronidase-deficient and lycopene producing E coli strains on formation of azoxymethane-induced aberrant crypt foci in the rat colon. Biochem Biophys Res Commun 262: 322–327, 1999.[Medline]
46. Kim DJ, Takasuka N, Kim JM, Sekine K, Ota T, Asamoto M, Murakoshi M, Nishino H, Nir Z, Tsuda H: Chemoprevention by lycopene of mouse lung neoplasia after combined initiation treatment with DEN, MNU and DMH. Cancer Lett 120: 15–22, 1997.[Medline]
47. Hecht SS, Kenney PM, Wang M, Trushin M, Agarwal S, Rao AV, Upadhyaya P: Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Lett 137: 123–130, 1999.[Medline]
48. Kim JM, Araki S, Kim DJ, Park CB, Takasuka N, Baba-Toriyama H, Ota T, Nir Z, Khachik F, Shimidzu N, Tanaka Y, Osawa T, Uraji T, Murakoshi M, Nishino H, Tsuda H: Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis 19: 81–85, 1998.[Abstract/Free Full Text]
49. Gradelet S, LeBon AM, Berges R, Suschetet M, Astrog P: Dietary carotenoids inhibit aflatoxin B1-induced liver preneoplastic foci and DNA damage in rats: role of modulation of aflatoxin B1 metabolism. Carcinogenesis 19: 403–411, 1998.[Abstract/Free Full Text]
50. LaVecchia C: Mediterranean epidemiological evidence on tomatoes and the prevention of digestive tract cancers. Proc Soc Exp Biol Med 218: 125–128, 1997.[Abstract]
51. Giovannucci E: Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 91: 317–331, 1999.[Abstract/Free Full Text]
52. Colditz GA, Branch LG, Lipnic RJ: Increased green and yellow vegetables intake and lowered cancer death in an elderly population. Am J Clin Nutr 41: 32–36, 1985.[Abstract/Free Full Text]
53. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC: Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87: 1767–1776, 1995.[Abstract/Free Full Text]
54. Gann P, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ: Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59: 1225–1230, 1999.[Abstract/Free Full Text]
55. Franceschi S, Bidoli E, LaVeccia C, Talamini R, D’Avanzo B, Negri E: Tomatoes and risk of digestive-tract cancers. Int J Cancer 59: 181–184, 1994.[Medline]
56. Potischman N, McCulloch CE, Byers T, Nemoto T, Stubbe N, Milch R, Parker R, Rasmussen KM, Root M, Grahm S, Campbell TC: Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A. Am J Clin Nutr 52: 909–915, 1990.[Abstract/Free Full Text]
57. Jarvinen R, Knekt P, Sppanen R, Teppo L: Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett 114: 251–253, 1997.[Medline]
58. Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ: Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J. Clin Nutr 66: 626–632, 1997.[Abstract/Free Full Text]
59. Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr: Relationship of serum carotenoids, retinol, -tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 9: 89–97, 1998.[Medline]
60. VanEewyck J, Davis FG, Bowen PE: Dietary and serum carotenoids and cervical intraepithelial neoplasia. Int J Cancer 48: 34–38, 1991.[Medline]
61. Helzlsouer KJ, Comstock GW, Morris JS: Selenium, lycopene, -tocopherol, ß-carotene, retinol, and subsequent bladder cancer. Cancer Res 49: 6144–6148, 1989.[Abstract/Free Full Text]
62. Parthasarathy S, Steinberg D, Witztum JL: The role of oxidized low-density lipoproteins in pathogenesis of atherosclerosis. Ann Rev Med 43: 219–225, 1992.[Medline]
63. Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP: Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273: 1849–1854, 1995.[Abstract]
64. Morris DL, Kritchevsky SB, Davis CE: Serum carotenoids and coronary heart disease: the Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. JAMA 272: 1439–1441, 1994.[Abstract]
65. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC: Vitamin E consumption and the risk of coronary heart disease in men. New Eng J Med 328: 1450–1456, 1993.[Abstract/Free Full Text]
66. Handelman GJ, Parker L, Cross CE: Destruction of tocopherols, carotenoids and retinol in human plasma by cigarette smoke. Am J Clin Nutr 63: 559–565, 1996.[Abstract/Free Full Text]
67. Kohlmeir L, Kark JD, Gomez-Gracia E, Martin BC, Steck SE, Kardinaal AFM, Ringstad J, Thamm M, Masaev V, Riemersma R, Martin-Moreno JM, Huttunen JK, Kok FJ: Lycopene and myocardial infarction risk in the EURAMIC study. Am J Epidemiol 146: 618–626, 1997.[Abstract/Free Full Text]
68. Kristenson M, Zieden B, Kucinskiene Z, Elinder LS, Bergdahl B, Elwing B, Abaravicius A, Razinkoviene L, Calkauskas H, Olsson A: Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50. BMJ 314: 629–633, 1997.[Abstract/Free Full Text]
69. Rao AV, Agarwal S: Effect of diet and smoking on serum lycopene and lipid peroxidation. Nutr Res 18: 713–721, 1998.
70. Kucuk O, Sakr FH, Djuric Z, Li YW, Velazquez F, Banerjee M, Bertram JS, Crissman JD, Wood DP: Lycopene supplementation in men with prostate cancer (Pca) reduces grade of preneoplasia (PIN) and tumor, decreases serum prostate specific antigen and modulates biomarkers of growth and differentiation. Intl Conf Diet Prev Cancer, Tampere, Finland, P1.13, 1999 (abstract).

This article has been cited by other articles:

				S. Devaraj, S. Mathur, A. Basu, H. H. Aung, V. T. Vasu, S. Meyers, and I. Jialal A Dose-Response Study on the Effects of Purified Lycopene Supplementation on Biomarkers of Oxidative Stress J. Am. Coll. Nutr., April 1, 2008; 27(2): 267 - 273. [Abstract] [Full Text] [PDF]

				L. J. Ignarro, M. L. Balestrieri, and C. Napoli Nutrition, physical activity, and cardiovascular disease: An update Cardiovasc Res, January 15, 2007; 73(2): 326 - 340. [Abstract] [Full Text] [PDF]

				A. Liu, N. Pajkovic, Y. Pang, D. Zhu, B. Calamini, A. L. Mesecar, and R. B. van Breemen Absorption and subcellular localization of lycopene in human prostate cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2879 - 2885. [Abstract] [Full Text] [PDF]

				S. A. Goff and H. J. Klee Plant Volatile Compounds: Sensory Cues for Health and Nutritional Value? Science, February 10, 2006; 311(5762): 815 - 819. [Abstract] [Full Text] [PDF]

				P. D. Matthews, R. Luo, and E. T. Wurtzel Maize phytoene desaturase and {zeta}-carotene desaturase catalyse a poly-Z desaturation pathway: implications for genetic engineering of carotenoid content among cereal crops J. Exp. Bot., October 1, 2003; 54(391): 2215 - 2230. [Abstract] [Full Text] [PDF]

				C. W. Hadley, S. K. Clinton, and S. J. Schwartz The Consumption of Processed Tomato Products Enhances Plasma Lycopene Concentrations in Association with a Reduced Lipoprotein Sensitivity to Oxidative Damage J. Nutr., March 1, 2003; 133(3): 727 - 732. [Abstract] [Full Text] [PDF]

				B. Demmig-Adams and W. W. Adams III Antioxidants in Photosynthesis and Human Nutrition Science, December 13, 2002; 298(5601): 2149 - 2153. [Abstract] [Full Text] [PDF]

				T. Rissanen, S. Voutilainen, K. Nyyssonen, and J. T. Salonen Lycopene, Atherosclerosis, and Coronary Heart Disease Experimental Biology and Medicine, November 1, 2002; 227(10): 900 - 907. [Abstract] [Full Text] [PDF]

				A. V. Rao Lycopene, Tomatoes, and the Prevention of Coronary Heart Disease Experimental Biology and Medicine, November 1, 2002; 227(10): 908 - 913. [Abstract] [Full Text] [PDF]

				P. V. Minorsky Plant Physiology, November 1, 2002; 130(3): 1077 - 1078. [Full Text] [PDF]

				E. S Ford, C. Gillespie, C. Ballew, A. Sowell, and D. M Mannino Serum carotenoid concentrations in US children and adolescents Am. J. Clinical Nutrition, October 1, 2002; 76(4): 818 - 827. [Abstract] [Full Text] [PDF]

				M. P. Mattson, S. L. Chan, and W. Duan Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior Physiol Rev, July 1, 2002; 82(3): 637 - 672. [Abstract] [Full Text] [PDF]

				M. Danilenko, X. Wang, and G. P. Studzinski Carnosic Acid and Promotion of Monocytic Differentiation of HL60-G Cells Initiated by Other Agents J Natl Cancer Inst, August 15, 2001; 93(16): 1224 - 1233. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, A. V. Articles by Agarwal, S. Search for Related Content PubMed PubMed Citation Articles by Rao, A. V. Articles by Agarwal, S.