papel do licopeno como antioxidante carotenoide na prevenção de doneças crônicas

8/12/2019 papel do licopeno como antioxidante carotenoide na preveno de doneas crnicas

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ELSEVIER

Nutrition Research, Vol. 19. No. 2, pp. 305-323.1999Copyright Q 1999 Elsevier Science In c.Rimed in the USA. All rights reserved

0271-5317/99/ +x front matterPIISO271-5317 98)00193-6

ROLE OF LYCOPENE AS ANTIOXIDANT CAROTENOIDIN THE PREVENTION OF CHRON IC DISEASES: A REVIEW

A. V. Rao, Ph.D. and S. Agarwal, Ph.D.Departm ent of Nutritional Sciences

Faculty of MedicineUniversity of Toronto

Toronto, ON MSS 3E2 CANADA

ABSTRACT

Lycopene is a naturally present carotenoid in tomatoe s. Among the carotenoids,lycopene is a major component found in the serum. High levels of lycopene havealso been found in the testes, adrenal glands, prostate. Several recent studiesincluding cell culture, animal and epidem iological investigations have indicated theeffect of dietary lycopene in reducing the risk of chronic diseases such as cancer andcoronary heart disease. A lthough, the antioxidant properties of lycopene are thoughtto be primarily responsible for its beneficial properties, evidence is accumulating tosuggest other mechanisms such as intercellular gap junction communication,hormonal and immune system modulation and metabolic pathw ays m ay also beinvolved. This review summarizes the background information about lycopene andpresents the most current knowledg e with respect to its role in human health.0 I999 ?3cviu Science IncKE Y WO RD S: Lycop ene, Carotenoids, Oxidative stress, Antioxidant, ChronicDiseases

INTRODUCTION

Cancer and cardiovascular diseases are the major causes of deaths in North A merica. Althoughgenetic fa ctors and age are important in determining the risk, dietary compon ent is also a majorrisk factor associated with the diseases (1). Approxim ately 70% of all cancers arejattributable todiet. Role of reactive oxygen species (RO S) and oxidative dam age to biomolecules is one of themain foci of recent research related to cancer and cardiovascular diseases. Oxidative stress hasbeen widely postulated to be involved in the causation and progression of several chronic diseases(2-8). Dietary antioxidants, which inactivate RO S and provide protection from oxidative dam age(2-8) are being considered as important preventive strategic molecules.Recent dietary guidelines to comba t chronic diseases including cancer and coronary h eart diseasesCorrespond ence address: Dr. A. V. Rao , Departm ent of Nutritional Sciences, Faculty of Medicine,University of Toronto, Toronto, ON Canada M 5S 3E2. Tel: 416-978 -3621, Fax: 416-97 8-3552,E-Mail: v.rao@,utoronto.ca


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306 A.V. RAO and S. AGARWAL

recomm end increased consumption of plant foods including fruits, vegetables, cereals andlegumes. This is in part due to epidemiological studies (international comparisons and cohortstudies) indicating a strong relationship between high calorie, high fat/meat diet, low fiber andincreased risk for many can cers (1,9). Plant foo ds are also rich sources of flavonoids, lignans andcarotenoids which in laboratory animal, cell culture, case control or cohort studies app ear toprotect against the development of cancer (10,ll). Micronutrient phytochem ical components ofplant foods have been suggested to have chemopreven tive activity possibly thro ugh their effect onhormonal metabolism and oxidative dam age (1).Recent epidemiological studies have recomm ended that high consumption of fruits and vegetablesreduces the risk of cancer. Carotenoids are plant pigments commonly found in fruits andvegetables and are considered to be the important micronutrients responsible for the protectiveeffects. Two competing hypoth eses have been propo sed to explain the anticarcinogenic carotenoidactivity: their ability as precursors of vitamin A or their intrinsic property as antioxidant. Non-provitamin A carotenoids such as lycopene or canthaxanthin also exhibit biological activity relatedto their cancer preventing effects. T his review will focus on the role of lycopene in human healthand disease.

CHEMISTRY

Carotenoids, in general, are mad e up of two tetraterpenes units joined by tail-to-tail bond. M ostcarotenoids have one or two ring structures (5 or 6 mem bered) formed by the cyclization of the endgroups. In addition to carbon and hydrogen, they may also contain oxygen atoms. Lycopen e is a 40carbon atom, open chain hydrocarbon containing 11 conjugated and 2 non-conjugated doublebonds arranged in a linear array 12) figure 1).

FIG. 1. Structure of LycopeneThese bonds can undergo isom erization from tram to mono or poly-cis isomers by light orthermoenergy or during chemical reactions. All frans, 5-c 9-cis, I3-cis and 15cis are the mostcommonly identified isomeric forms of lycopene. Since lycopene lacks P-ionone ring structure itlacks provitamin-A activity. Molecular formula is (C40 H56 ) and the molecular weight is 536.85daltons. Lycopene is a lipophillic compou nd and is insoluble in water. It is a red pigment, absorbslight in the visible range and petroleum ether solution of lycopene has h,, 472 mn and E%3450.

DIETARY SOURCES

Lycopen e, like other carotenoids, is a natural pigment synthesized by plants and microorganisms toabsorb light during photosynthesis and to protect them against photosensitization. Red fruits and


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LYCOPENE AND CHRONIC DISEASE 307

vegetables are the most common sources of lycopene. Tomatoes and tomato b ased productsaccount for more than 85% of the dietary lycopene in North A merica. Watermelon, pink grapefruit,apricots, pink guava and papaya are also rich sources of lycopene (13-17) Table 1). The lycopenecontents in tomato es differs with tomato varieties and increase with fruit ripening (17). All-truns isthe predominant isomeric form of lycopene in raw tomatoe s but tram to cis isomerization occursduring cook ing/food processing and storage (18). Loss of lycopene contents appea rs to be minimalduring cooking or food processing (15-18). T omato juice, ketchu p, soup and tomato b ased pizzaand spaghetti sauce a re the major contributor of lycopene in diet (13-l 9) Table 2).

Table 1. Lycopene contents of common fruits and vegetables (13-17).Fruits I Vegetab les Lycopene @g /g wet weight)

Tomatoes 8.8 - 42.0Water melon 23.0 - 72.0Pink Guava 54.0

Pink Grapefruit 33.6Papaya 20.0 - 53.0Apricot < 0.1

Table 2. Lycopene contents of common tomato based foods (13-19).Tomato Products

Fresh TomatoesCooked TomatoesTomato SauceTomato Paste

Tomato Soup (condensed)Tomato Powder

Tomato JuicePizza Sauce

Ketchup

Lycopene @g/g weight)8.8 - 42.037.0

62.054.0 - 1500.0

79.91126.3 - 1264.9

50.0 - 116.0127.1

99.0 - 134.4

UPTAKE. M ETABOLISM AND TISSUE DISTRIBUTION

Carotenoids detectable in different human tissues are of dietary origin. In a recent study, whensubjects con sumed tomato free diet for two week s, their lycopene levels dropp ed significantly (20).Ingested carotenoids including lycopene a re incorporated into dietary lipid micelles. ab sorbed intothe intestinal mucosal lining via passive diffusion. They are incorporated into chylomicrons andreleased into lymphatic system for transport to the liver. Carotenoids are transported by thelipoproteins into the plasma for distribution to the different organs (21 ). Many fa ctors influenceabsorption and hence bioavailability of dietary lycopene. Release of lycopene from the food matrixdue to processing, presence of dietary lipids, heat induced isomerization from all tram to cisconformation enhance the bioavailability (22). Ingestion of cook ed tomato juice in oil mediumincreased serum lycopene levels by three fold whe reas consumption of an equivalent amount o f


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308 A V RAO and S AGARWAL

unprocessed juice did not have any effect (22). In a recent study, lycopene from tomato paste wasshown to be more bioavailable than from fresh tomato es (23). There are indications that cisisomeric form is more bioavailable than tram (22). Absorption of lycopene seem to be moreefficient at lower dosages. Also, lycopene when ingested w ith p-carotene was absorbed more thanwhen ingested alone (24). Information regarding the relationship between dietary lycopene(calculated or estimated) and serum or tissue lycopene levels is lacking.Serum lycopene levels are affected by several biological and lifestyle facto rs. Fasting serumlycopene levels were found to be higher and more reproducible than post prandial levels indicatingthe diet induced metabolic stress (20). Lycopene levels in blood do not differ significantly betweenmen and wom en (25,26). In wom en, blood lycopene levels were found to be affected by the phasesof menstrual cycle with a peak during mid-lute phase (27 ). Controversial results were reported onthe effects of smoking on serum lycopene levels (25,28 ,29). In a recent study (20 ), it was foundthat there were no significant differences in serum lycopene levels between smok ers and non-smok ers. How ever, the serum lycopene levels fell by 40% with a 40% increase in lipidperoxidation in smok ers immediately following smoking three cigarettes (20). Similarly in-vitroexposu re of fresh plasma to cigarette smok e depleted lycopene and several other lipophilicantioxidants (30). Alcohol consumption has also been found to alter serum lycopene levels (25).Lycopen e is the most predominant carotenoid in human plasma and has a half life of about 2-3days (3 1). In human plasma, lycopene is an isomeric mixture containing 50% of the total lycopeneas cis isomers. The most prominent geom etric isomers from plant sources are al2 trans. There aresome indications of in-vivo tram to cis isomerization reactions (32). Very little is known about in-vivo metabolism of lycopene. Only a few metabolites, such as 5,6-dihydroxy-5,6-dihydro lycopene,have been detected recently in human plasma (33,34). It was suggested that lycopene may undergoin-vivo oxidation to form epoxides which then may be converted to 5,6-dihydroxy-5,6-dihydrolycopene through metabolic reduction (33,34). Owing to its lipophilic nature lycopene w as foundto concentrate in LD L and VLD L fractions and not in HD L fraction of the serum (3 1).

Table 3. Lycopene levels in human tissues (36-42).TissueTestes

AdrenalProstate

LiverBreast

PancreasLung

KidneyColonSkin

OvaryStomach

Brainstem

Lycopene (nmoYg wet wt)4.34 - 21.361.9 - 21.60

0.81.28 - 5.72

0.780.7

0.22 - 0.570.15 - 0.62

0.310.420.30.2

not detectable


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Lycopen e is known to accumulate in human tissues. Prolonged and excessive consumption oftomato juice increased serum lycopene levels and resulted in coloration of skin and liver, acondition identified as lycopenemia (35). Tissue distribution of dietary carotenoids includinglycopene is not uniform. Tissue specific carotenoid distribution suggest that certain carotenoidsmay exert a unique biological effect in some tissues but not in the others. Table 3 shows thelycopene levels in human tissues reported by different investigators (36-42).How ever, inter-individual variations in reported tissue-lycopene levels are about 100 fold. Adiposetissues may se rve as a marke r for the assessment of body lycopene status since they are a potentialsource of easily available biological material. Lycopene was found to concentrate and be the mostprominent carotenoid in adrenal glands, testes, liver and prostate (36-42). T he exact biochemicalmechanism for the high concentration in these tissues is not clear. One hypothesis is that thesetissues have large number of lipoprotein receptors and lycopene is mainly transported throughlipoprotein (37). Lycopene and other carotenoids have been recently identified in several bodyfluids. 34 carotenoids including 13 geom etric isomers and 2 lycopene o xidation products warerecently reported in human milk (33). Lycopene and P-carotene were also found in human seminalplasma and their levels were lower in imrmmoinfertile men compare d to normal individual (43).

BIOCHEMICAL EFFECTS

Although, the effect of lycopene on the reactivity of RO S has been studied extensively its effectson metabolic processe s have also been reported.Oxidative Effects:Endogenous or exogenously generated RO S have been implicated in the pathogenesis of varioushuman diseases (2-8). Consumption of carotenoid rich food is often associated with several healthbenefits. Mo st of the important health benefits are hypothe sized to occur through their ability toprotect against oxidative dam age. In-vitro studies have indicated that lycopene is an effectiveantioxidant and radical scav enger (44-46). L ycopene, because of its high number of conjugateddienes, is the most potent singlet oxygen quen cher among natural carotenoids (46). Lycopene wasalso reported to inactivate hydrogen peroxide and nitrogen dioxide (47,48). M ortensen et al (49)using pulse radiolysis technique demo nstrated carotenoids ability to scavenge nitrogen dioxide(NO z*), thiyl (RS ), and sulphonyl (RSO ;) radicals. In recent studies, lycopene was found to be atleast twice as active as p-carotene in protecting lymphocytes against NO* radical inducedmem brane dama ge and cell death (48,50). Th ere are indications that lycopene is the most potentscavenger of RO S among other major dietary carotenoids (46,49). In-vivo antioxidant effects oflycopene and its interaction with host and other dietary antioxidant defenses are beginning to beinvestigated. Lycopene is extremely hydropho bic and is most commonly located within cellmem branes and other lipoprotein components. Interactions of lycopene w ith RO S is thereforeexpec ted to be more profound in a lipophilic environment. Lycopene protected human LD L againstphotosensitized oxidative dam age (5 1). Skin lycopene was destroyed preferentially over P-caroteneduring ultraviolet light exposu re in humans suggesting a superior role of lycopene over p-carotenein mitigating oxidative dam age in tissues (52).


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Non-oxidative:Carotenoids ability to induce gap junctional communication between cells has also been suggestedto be a potential basis for their protective effects towa rds cance r development. Lycopene is shownto be capable of improving cell to cell communication, but its effects are less pronounced than p-carotene or canthaxanthin (53). A recent study reported differential dose related effects of p-carotene and lycopene .on gap junctional communication in rat liver. Very low doses (0.5 mgk gb.w.) had no effect where as medium dose (5 mg/kg b.w.) was enhancing and very high dose (50mg/kg b .w.) was inhibiting gap junctional communication in rat liver in vivo (54). It appea rs thatthe gap junctional communication ability of carotenoids and their singlet oxygen quenchingabilities or antioxidant properties are independent of each other (55). Lycopene has been found toact as a mod erate hypocho lestremic agent and this effect is related to the inhibition of 3-hydroxy-3-methyl glutaryl coenzyme A (HM GC oA) reductase, the rate limiting enzyme in cholesterolsynthesis (56). Lycopene has also been sugge sted to have modulating effects on liver drugmetabolizing enzyme cytochrome P-450 2El (57).

ROLE OF LYCOPENE IN HUMAN HEALTH

Lycopen e, a predominant carotenoid in tomato es, ex hibits highest antioxidant activity among alldietary carotenoids. Its potential role in human health is beginning to be recognized (3 1,58,59).The main supporting evidences come from three different rese arch directions: (a) tissue culturestudies u sing differen t cell lines to investigate anti cell prolifera tive activities, (b) use of animalmode ls to study anti tumorogenic properties of lycopene and (c) epidemiological studies done withcontrol and at risk population.Tissue culture studies:Tissue culture systems have provided unique evidence for molecular and biochemical effects oflycopene in normal and malignant cell lines. S o far the wo rk has mainly concentrated onantitumorogenic activity of lycopene. Table 4 provides an updated list of the cell culture studies onthe role of lycopene.Lycopen e caused about 40% inhibition in cell grow th in human leukemia cell lines (60), more overwhen adde d with retinoic acid, which ca uses cellular differentiation, it potentiated the effects (61).In C3W lOT1/2 mouse embryo fibroblast cell line, lycopene inhibited the methylcholanthreneinduced malignant transformation (62). Lycopene was also shown to enhance th e expression ofconnexin43, a gene encoding major gap junction protein, and thereby up regulated gap junctioncommunication and acted as anticarcinogen (53,63). Improved survival and suppression of lipidperoxidation in CC 14 expo sed rat hepatocy tes was observed by lycopene treatment (64). Lycopenealso protected the mouse hepatocy tes microcystin-LR, a liver tumor promo ter (65). The retinoidsand a-tocopherol show ed none to very little effects in the same system. It was hypothe sized thatlycopene might have arrested Go/G1 cell cycle phase by suppressing carcinogen inducedphosphorylation of regulatory proteins such as ps3 or Rb antioncogene by non-oxidativemechanism (65). In an in-vitro study using Raji cells (Epstein-Barr virus genome carryinglymphoblastoid cells) lycopene inhibited 12-O-tetradecanoylph orbol-13-acetate induced Epstein-Barr virus activation almost as much as p-carotene (66). Lycopene was a powerful inhibitor of


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endometrial (Ishikawa), mam mary (MC F-7) and lung (NCI-H 226) human cancer cells proliferationand suppressed insulin-like grow th factor-I-stimulated grow th. a- and p-carotene were far lesseffective inhibitors, how ever, normal fibroblast were far less sensitive to lycopene (67). In a recentstudy, using J-774 A.1 mac rophag e cell line lycopene as well as p-carotene suppress ed 60-70% ofcholesterol synthesis by acetate and were implicated as mod erate hyp ocholesterem ic agent (56).

Table 4. Anticarcinogenic and other effects of lycopene in cell cultureInvestigators

Countryman et al.601

Bankson et al. (61)Bertram et al. (62)Zhang et al. (53,63)Kim (64)Matushim a et al.(65)Tsushima et al. (66)Levy et al. (67)

Fuhrman et al. (56)

Cell typeHL-60 human leukemia celllineHL-60 human leukemia celllineC3H/lOT1/2 mouse embryofibroblast cell lineC3H/lOT1/2 mouse embryolibroblast cell lineRat hepatocytesMouse hepatocytesRaji cells

Major FindingsLycopene (10 umol/L) caused 40%reduction in cell grow th.Lycopene enhanced the differentiatingeffects of retinoic acid.Inhibition of malignant transform ation.Enhancement of connexin43 geneexpression.Reduced the CC1 4 poisoning.Protected against microcystin-LRinduced liver tumors.Inhibited the activation of genes.

Human cancer cell linesendometrial (Ishikawa)mammary (MCF-7)lung (NCI-H226)normal fibroblastJ774 A. 1 mac rophag e cell line

Lycopene suppressed the growth ofcancer cells but not of normal fibroblast.

Lowered cholesterol synthesis byinhibiting HMGCoA reductase

Animal studies:Animal m odels have provided excellent sy stem to investigate in-vivo biochemical functions oflycopene in a well defined, controlled environment whe re the confounding variables are minimum.Radioprotective as well as antibacterial activities of lycopene were established almost 40 years agousing laboratory mice (6869). Dietary lycopene increased th e survival rate of mice expo sed towhole body x-irradiation (68). Intraperitonial injections of lycopene also protected the mice frombacterial infections and inhibited the development of ascites tumors (69). Table 5 provides a listof studies don e using animal model systems.Lycopene inhibited the grow th and development of C-6 glioma cell (malignant brain cells)transplanted into rats (70). Grow th inhibitory effects were more pronounced when lycopene w asgiven before the glioma cells inoculation. Chronic intake of lycopene markedly delayed onset andreduced spo ntaneous mam mary tumor grow th and development in SH N virgin mice (71). Thiseffect was associated with reduced activity of mam mary gland thymidylate synthetase and loweredlevels of serum free fatty acids and prolactin, a hormone known to be involved in breast cancer


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development by stimulating cell division. Lycopene was also shown to enhance theimmunoresponse by increasing helper T cells and normalizing the intraathymic T celldifferentiation caused by tumorogenesis in SH N retired mice (72). Lycopene and lutein at smalldoses reduced the N-methylnitrosourea (MN U) induced developm ent of aberrant crypt foci (ACF)in Spargue-D awley rats (73). In a dimethyl benzanthracene (DM BA ) induced m amm ary tum ormodel of rats, intraperitoneal injections of lycopene enriched tomato oleoresin but not of p-carotene suppress ed tumor g rowth in size and tumor numbers (74). Dietary lycopene dissolved indrinking water at 50 ppm dose significantly decreas ed the diethylnitrosamine, methylnitrosoureaand dimethylhydrazine (DM D) induced incidences and multiplicities of lung adenom as pluscarcinomas in male mice (75). The protective effects wer e how ever, not observed in female m iceor in the colon or kidney in the same study (75). Diethylnitrosamine (DE N) induced liver

Table 5. Protectiv e effects of lycopene demo nstrated in animal studies

preneoplastic foci in rats were significantly reduced by dietary lycopene and not by any othercarotenoid tested (57). Lycopene howe ver h ad no effects on 2-nitropropane inducedhepatocarcinogenesis. It was hypothes ized that lycopene provided protection thro ugh itsmodulating effect on the liver enzymes activating diethylnitrosamine, cytochrom P-450 2E 1, andnot through an tioxidative mechanism (57). Lycopene had no protective effect ondimethylhydrazine (DM H) induced colon carcinogenesis in mice as indicated by proliferation ofcolonic crypt epithelial cells as well as BrdU incorporation assay (76). Lutein and fucoxanthin had


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significant protection in the same carcinogenesis model (76). Ingestion of tomato juice inhibitedthe development of N-butyl-N-(4-hydroxybutyl)nitrosamine (BB N) induced development o furinary bladder transitional cell carcinomas in male Fischer 34 4 rats (77). Aflatoxin Bl-inducedliver preneoplastic foci in rat were not affected by dietary lycopene whe reas p-carotene providedsignificant protection (78). Recent investigations in our lab indicated that dietary lycopene (1 0ppm ) significantly reduced the lipid and protein oxidation and demon strated an apparent p rotectiveeffect against azoxym ethane induced colonic preneoplastic lesions in rats (Rao et al. unpublished).Epidemiological studies:The interest in lycopene and its potential protective role in prevention of chronic diseases stemslargely from the epidemiological observations on normal and at risk populations. The presentknowledg e largely relies on the data obtained from dietary estimates or plasma values in relation tochronic diseases. Various epidemiological studies have sugg ested that a diet rich in a variety offruits and vegetables results in a lower risk of cancer and other chronic diseases (79,80). An earlyepidemiological study on elderly Americans indicated th at high intake of tomatoe s was associatedwith a significant reduction of mortality from cancers at all sites (81). Epidemiologicalinvestigations to study the role of lycopene in relation to chronic diseases has focused primarily oncancers. Epidemiological studies showing a relationship between lycopene and chronic diseasesare listed in Table 6.

Table 6. Lycop ene and chronic diseases in epidemiological studies.Investigators

Giovannucci et al. (82)

Franceschi et al. (83)

VanEewyck et al. (84)Helzlsour et al. (85)

Dorgan et al. (89)Kohlmeier et al. (93)

Kristenson et al. (95)

Coodley et al. (96)Periquet et al. (97)Schm idt et al. (98)

Type of Study Ma jor FindingsProspective Co hort Dietary intake of tomato productsProstate cancer inversely associated with prostate

cancer riskCase control study high intake tomato was associated toDigestive tract reduced risk of all types of digestivecancer tract cancerCase control study only lycopene show ed an inverseCervical cancer association with cervical cancer riskCase control study serum lycopene associated withBladder cancer decreased riskCase control study inverse association between serumBreast cancer lycopene and breast cancer riskCase control study adipose tissue lycopene associatedMyo cardial with lowered riskInfraction riskCross sectional low serum lycopene associated withpopulation increased mortality from heartMortality from diseasechronic heart diseaseHIV positive women lower serum lycopene levels in casesand infected childrenElderly population lower serum lycopene in high riskcerebrovascular individualsdisease risk


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An inverse association between high intake of tomato products (based on food frequencyquestionnaire) and prostate cancer risk was confirmed in US Health Professionals Follow-up Study(82). The estimated intakes of total carotenoid, p-carotene, o-carotene, lutein and P-cryptoxanthinwere not associated with the risk factor. Higher estim ated lycopene intake was inversely related torisk of prostate cancer. A lmost 35% risk reduction was observed based on consumption frequencyof more than 10 servings of tomato products per wee k and the protective effects w as even strongerwhen the analysis was focused on more advanced or aggressive prostate cancer (8 2). In a case-control study (cases we re the patients with histologically confirmed cancers of oral cavity,pharynx, esopha gus, stomach , colon and rectum and controls w ere the patients with unrelatedconditions) in Italy, high lycopene intake was consistently associated with reduced cancer risk ofall sites, and especially of stoma ch, colon and rectum (83). A case-control study comparing womenwith cervical interepithelial neoplasia with normal controls, repo rted that among all dietarycarotenoid intake and serum carotenoid concentrations, only lycopene show ed an inverseassociation with the risk (84). Serum lycopene levels were also found to be inversely related to therisk of bladder cancer (8 5). An inverse association to no association between lycopene (estimatedintakes or serum levels) and breast cancer risk were reported by several investigators (86-88). In arecent case control study nested a cohort from the Breast Cance r Serum B ank in Columbia MO ,only serum lycopene and non of the other carotenoids or a-tocopherol show ed a significant inverserelationship with breast cancer risk (89).Coronary heart disease has also been shown to be the major cau se of morbidity and mortality inWestern w orld. There is extensive evidence that oxidatively modified low-density lipoproteins areinvolved in the initiation and promotion of atherosclerosis (5). It has been suggested that dietaryantioxidant vitamins and carotenoids may protect low-density lipoproteins from oxidative dam ageand may thus contribute to reducing the risk of atherosclerotic vascular disease (7,s). How ever,many dietary intervention trials involving a-tocophero l or p-carotene have yielded inconclusiveresults (90-9 2). Very little work has been done on lycopene. In a multicenter case-control studyconducted in 10 European countries (EUR AM IC study) to evaluate the relations betweenantioxidant status assessed in adipose tissue biopsies and acute myocardial infraction, it wasconcluded that lycopene and not p-carotene, contribute to the protective effect of vegetableconsumption (93,94). The protective potential of lycopene was maximum among individuals withhighest polyunsaturated fat stores, supporting the antioxidant theory (93). Similarly, lower serumlycopene levels were found associated with increased risk and mortality from coronary heartdisease in a cross sectional study comparing Lithuanian and Swe dish populations showingdiverging mortality rates from coronary hea rt disease (95). Low er serum lycopene levels were alsoreported in human immunodeficiency virus (HIV) positive wom en and also in children infectedwith HIV (96,97). L owe r levels of serum lycopene and a-tocopherol were also reported inindividuals from an elderly population at high risk for microangiopathy-related cerebral dama ge (arisk factor for cerebrovescular disease) in Austrian stroke prevention study (98).Dietarv suuplementation studies:Since lycopene is available in very limited number of food sources, a precise and accurate intakecalculations from food frequency questionnaire can be perform ed. How ever, the vastepidemiological data provides only a suggestive evidence rather than a proof of a causalrelationship of lycopene intake and risk of chronic diseases. To date, practically no intervention


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trials have been perform ed investigating the effectiveness of lycopene intake on lowering the riskof chronic diseases. Ingestion of lycopene free diet for two weeks resulted in 50% loss of serumlycopene with a 25% increase in in-vim lipid oxidation in healthy human subjects (20). In a smallclinical trial, lycopene was found to act as a mod erate hypocholesterimic agent (56). Studiesinvolving healthy human subjects in our laboratory indicated tha t lycopene from traditional tomatoproducts is absorbed readily, increases serum levels and lowers the oxidative dam age to lipids,lipoproteins, proteins and DN A (Agarw al & Rao , submitted for publication) Figure 2). The levelof consumption of tomato products used in this study were about one or two servings/day, wereeasily achievable and were in keeping w ith the current dietary recommen dations pertaining tohealthy eating.

0 LycopeneE Serum TBARSEZEI LDL TBARSIX57 DL CDm Thiols

8 OHdG

50 Sauce Juice OleoresinFIG . 2. Effect of lycopene supplementation on serum lycopene and the levels oflipid, protein and DNA oxidation. Dietary lycopene was provided to healthyhuman subjects in the form of spaghetti sauce (Sauce), tomato juice (Juice) ortomato oleoresin (Oleoresin) with a standardized breakfast for a period of one wee kin a random order. Fasting blood was collected at the end of each treatment. Serumlycopene was extracted by hexane and analyzed by HP LC. S erum lipid oxidationwas estimated by measuring total serum TBA RS (Serum-T BAR S), isolated serumLDL TBAR S (LDL-TBA RS) and isolated LDL conjugated dienes (LDL-CD).Serum protein ox idation was estimated by measuring reduced thiol groups in serumproteins (Thiols). Lymphocytes DNA oxidation was estimated by HPL Cmeasurement of &hydroxydeoxyguanosine (8-OHdG).

CONCLUSION

Dietary guidelines for the prevention of cancer and coronary heart disease recomm end increasedconsumption of plant foods that include fruits, vegetables, cereals and legumes. Presence ofmicronutrient phytochem ical compou nds are now being recognized as playing an important role inthe disease prevention properties of the plant foods, possibly through their effect on hormonal


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metabolism and oxidative dam age. Lycop ene, a carotenoid antioxidant, has been shown in recentepidemiological and experimental studies to protect against oxidative dam age and contributetowa rds reducing the risk of cancer and coronary heart disease. In addition to its antioxidantmediated activity, other metabolic effects of lycopene have also been demo nstrated. Base d oncurrent kno wledge the role of lycopene in human health is summ arized in Figure 3.

1ood Processing

FIG . 3. Role of lycopene in human health

Further studies are required to gain a better understanding of the role of lycopene in human health.Processing has traditionally been considered as contributing towar ds the loss of nutritional qualityof foods. The re is, how ever, indication that in the case of lycopene processing might actuallyenhanc e its bioavbialbility and nutritional quality. Although it is generally recog nized that hea ttreatment of tomatoe s induces the formation of cis-isomers from the all trans form present in rawtomatoe s, specific types of isomers formed and their biological significance is not fullyunderstood. Bioavailability of lycopene is influence not only by its isomeric form but also thepresence of other dietary components including dietary fat, other carotenoids, vitamins andminerals. These factors should be evaluated in an attempt to maximize lycopene absorption fromthe diet. Another area of future research should include elucidation of mechanisms other thanantioxidant properties of lycopene in the prevention of chronic diseases. Preliminary data suggeststhe possibilities of these alternate pathw ays of lycopene activity. Finally, long term humanintervention studies should be carried ou t with populations at risk for cancer and coronary heartdisease. Based on the results from these studies an effective dietary strategy can be developed forthe managem ent of chronic diseases in humans that will be based on increased consumption oflycopene containing foods.


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317YCOPENE AND CHRONIC DISEASE

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papel do licopeno como antioxidante carotenoide na prevenção de doneças crônicas

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