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Am J Clin Nutr 2000; p1691s

Am J Clin Nutr 2000; p1691s

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ABSTRACT
Considerable evidence suggests that lycopene,a carotenoid without provitamin A activity found in high con-centrations in a small set of plant foods,has significant antioxi-dant potential in vitro and may play a role in preventing prostatecancer and cardiovascular disease in humans. Tomato products,including ketchup,tomato juice,and pizza sauce,are the richestsources of lycopene in the US diet,accounting for >80% of thetotal lycopene intake of Americans. Unlike other carotenoids,lycopene is not consistently lower among smokers than amongnonsmokers,suggesting that any possible preventive activity isnot as an antioxidant. Instead,lycopene may have a cholesterolsynthesis-inhibiting effect and may enhance LDL degradation.Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adi-pose tissue concentrations of lycopene. The question of whetherlycopene helps to prevent cardiovascular disease can only beanswered by a trial specifically evaluating its effectiveness inthis area.
 Am J Clin Nutr 
2000;71(suppl):1691S–5S.
KEY WORDS
Lycopene,cardiovascular disease,carotenoid,antioxidant,LDL
INTRODUCTION
Lycopene is a hydrocarbon carotenoid that has recently receivedattention for its potential role in preventing prostate cancer and car-diovascular disease in humans. Although similar in structure to themore studied
-carotene,lycopene does not have provitamin Aactivity. The many conjugated double bonds of carotenoids makethem potentially powerful antioxidants,and lycopene is no excep-tion. Indeed,in 1989 Di Mascio et al (1) showed that lycopenehad the strongest singlet oxygen-quenching capacity of severalcarotenoids,with
-carotene,
-carotene,and lutein next in capac-ity. The weakest singlet oxygen quencher of the antioxidants stud-ied was
-tocopherol,which is found in much greater concentrationsin many body systems. In the past,this difference in concentrationdrew attention away from the carotenoids as antioxidants,andcarotenoids have been studied in detail only recently.Largely because it can be converted to vitamin A,
-carotenehas been the most intensely studied carotenoid to date. A signi-ficant accumulation of observational evidence suggesting that
-carotene,or foods rich in
-carotene,may protect againstcancer led to several clinical trials involving
-carotene supplemen-tation (2,3). However,these trials showed that
-carotene sup-plementation either increased or had no effect on the risk of lungcancer in high-risk subjects (4–6).The deleterious effects of 
-carotene supplementation are notrestricted to lung cancer. Rapola et al (7) found that persons con-suming
-carotene supplements had a 75% increase in fatal coro-nary heart disease in a comparison with persons not receivingsupplements. These researchers found a borderline-significantincrease in total coronary events in the
-carotene–supplementedgroup but no significant increase in nonfatal coronary events.Although the results of observational studies seem to suggestthat intake of foods rich in
-carotene (ie,fruit and vegetables)protects against such chronic diseases as cancer and cardiovas-cular disease,clinical trials have not found
-carotene to be pro-tective and,in some cases,have even shown a negative effect.This suggests that carotenoids other than
-carotene may beimportant in preventing disease or that
-carotene is actingthrough some mechanism beyond that of antioxidation.
FOOD SOURCES AND ABSORPTION OF LYCOPENE
Lycopene is a fat-soluble pigment that gives tomatoes,guava,pink grapefruit,watermelon,and a limited number of other foodstheir red color. More than 80% of the US dietary intake of lycopene is estimated to come from tomato sources,includingketchup,tomato juice,spaghetti sauce,and pizza sauce (8).Tomatoes also contain a significant amount of 
-carotene. Infact,they are the fourth-leading contributor to provitamin A andvitamin A intake in the American diet (9). Tomatoes are also richin folate and potassium,and there is almost 3 times as much vita-min C as lycopene in a tomato. Thus,in studies of health bene-fits of tomatoes,one must consider that they are also rich innutrients other than lycopene.The mechanism of absorption of lycopene is not completelyunderstood. Studies have shown that lycopene from tomato prod-ucts appears more readily in the circulation if the tomato isheated and if a source of fat is included with the meal. Plasmalycopene concentrations increased only slightly in a groupreceiving 180 g tomato juice (containing 12 mg lycopene) dailyfor 6 wk (10). This finding is supported by other studies show-
 Am J Clin Nutr 
2000;71(suppl):1691S–5S. Printed in USA. ©2000 American Society for Clinical Nutrition
Lycopene and cardiovascular disease
1–3
 Lenore Arab and Susan Steck 
1691S
1
From the School of Public Health,University of North Carolina,Chapel Hill.
2
Presented at the 17th Ross Research Conference on Medical Issues,heldin San Diego,February 22–24,1998.
3
Address reprint requests to L Arab,2105e McGavran Greenburg,School of Public Health,CB #7400,University of North Carolina,Chapel Hill,NC 27599-7400. E-mail:lenore@unc.edu.
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ing negligible or only slight increases in plasma lycopene con-centrations after consumption of various amounts of unheatedtomato juice (11,12). In one study,however,when heatedtomato juice mixed with oil was consumed,serum concentra-tions of lycopene increased,with a peak 24–48 h after ingestion(12). Similarly,Gartner et al (13) found that concentrations of lycopene in the chylomicrons of 5 human subjects increased
3 times as much when they consumed tomato paste as whenthey consumed raw tomatoes. Thus,the availability and absorp-tion of lycopene depend on the processing and treatment of thefood that contains the carotenoid and on the fat content of themeal in which lycopene is consumed.Because of the abundance of double bonds in its structure,thereare potentially 1056 different isomers of lycopene,but only a frac-tion are found in nature (14,15). The
all
-
trans
-configuration is theusual form of carotenoids,including lycopene,in foods (8). How-ever,Stahl et al (16) found that heating tomato juice resulted in
trans
-to-
cis
isomerization of lycopene,and on ingestion of this juice,the
cis
isomers of lycopene appeared to predominate inhuman serum over the
all
-
trans
isomers. Results from the study byGartner et al (13) showed that more than half of total lycopene inhuman serum is in the
cis
form. At present,the exact functions andrelative activities of these different isomers are unknown.
LYCOPENE AND SMOKING
Cigarette smoking is a well-known risk factor for coronary ath-erosclerosis. One theory of its mechanism of action is that smokeintroduces a source of free radicals into the body,which causeLDL oxidation,leading to foam cell production and atherogenesis.Studies suggest that the severity of atherosclerosis is related toheightened susceptibility of LDL to oxidation (17). Thus,antioxi-dants that can protect LDL from oxidation may also protecthumans against coronary heart disease. Smokers have beenshown to have lower plasma concentrations of most carotenoids(by 18–44%) than nonsmokers (18–21). In the Alpha-Toco-pherol,Beta-Carotene Cancer Prevention Study,subjects whosmoked the most (
20 cigarettes/d) generally had lower serumcarotenoid concentrations than did those who quit smoking orsmoked <20 cigarettes/d (22). The relation between smokingand serum concentration of lycopene was not consistentlyinverse,however.Human plasma directly exposed to gas-phase cigarette smokefor 9 h showed an 80% decline in lycopene concentration (23). Theorder of depletion of dietary antioxidants was as follows:lycopene>
-tocopherol >
trans
-
-carotene > lutein/zeaxanthin=cryptox-anthin >
-tocopherol=retinol. In an observational study (
n
=91),Pamuk et al (19) found that African American female smokershad 26% lower serum lycopene concentrations than did non-smokers after adjustment for dietary intake of lycopene and otherpotential confounders.The design and results of the study by Pamuk et al are sum-marized in
Table 1
(19),as are 5 other studies in which no effectof smoking on plasma lycopene concentrations was found. Penget al (24) found that plasma concentrations of 
-carotene,
-carotene,lutein,zeaxanthin,cryptoxanthin,and
cis-
-carotene,but not lycopene,were lower in smokers than in nonsmokers evenat the same level of intake. In another study,Brady et al (25)found that serum lycopene was not significantly lower in smokersthan in nonsmokers,even though dietary intake of lycopene waslower in smokers. Rao and Agarwal (26) also reported that serumlycopene concentrations did not differ significantly between non-smokers and habitual smokers. In a sample of men aged 25–55 y,no significant differences in plasma lycopene concentrationswere observed between smokers,tobacco chewers,and nonusers(27). Hininger et al (28) also found no significant difference in1692SARAB AND STECK
TABLE 1
Lycopene concentrations by smoking statusLycopeneLycopeneFactors controlledAuthorsSample
n
concentrationdietary intakefor in analyses
nmol/L
g
Pamuk et al (19)African American women,3069 y old,50 nonsmokers348
1
44.2
±
8.1
2
Age,energy intake,nutrient intake,serum concentrations41 smokers257
3
31.6
±
9.0supplement intake,alcohol intake,medication,BMI,serum cholesteroland serum triacylglycerolsPeng et al (24)Healthy whites,2682 y old,62 nonsmokers606
±
257
2
Data not shownAge,sex,diet intake estimates,plasma concentrations34 smokers606
±
312and vitamin supplement useBrady et al (25)Men and women,
50 y old,186 never smokers418 (384,456)
4
320 (280,366)Noneserum concentrations133 past smokers441 (402,483)366 (327,410)81 current smokers443 (393,500)233 (166,326)Rao and Healthy men and women,25–40 y old,? nonsmokers573.53
±
107.51
5
Data not shownSubjects matched by age and sexAgarwal (26)serum concentrations? smokers593.98
±
98Driskell et al (27)Men,2555 y old,10 nonusers692
±
369
2
1403
±
3300Noneplasma concentrations23 smokers545
±
3111021
±
126411 tobacco chewers760
±
6371963
±
3345Hininger et al (28)Healthy men and women,2545 y old,11 nonsmokers610
±
300
2
Data not shownNoneplasma concentrations11 smokers560
±
240
1
Geometric mean.
2
 x
±
SD.
3
Significantly different from nonsmokers,
P
=0.03.
4
Geometric mean; 95% CI in parentheses.
5
 x
±
SEM.
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plasma lycopene concentrations between a sample of 11 smokersand 11 nonsmokers. Thus,there is evidence that smoking status isnot inversely related to circulating concentrations of lycopene inhumans.Rao and Agarwal (26) studied the effect of smoking and dieton serum lycopene concentrations in humans. Postprandial serumconcentrations of lycopene were always lower than fasting serumlycopene concentrations,suggesting the use of lycopene to com-bat a meal-induced metabolic stress. Similarly,serum lycopeneconcentrations decreased by an average of 40% immediately aftersubjects smoked 3 cigarettes in 30 min. A corresponding increasein TBARS (thiobarbituric acid-reactive substances,a measure of lipid oxidation) of the same proportion supports an antioxidantfunction of lycopene in vivo. Thus,the results are mixed,and therelation between lycopene and smoking is not clearly understood.
BIOLOGICAL ACTIVITY OF LYCOPENE
Several studies examined the relation between dietary intakeof antioxidants and lipid peroxidation to try to determine whichantioxidants may play a role in preventing cardiovascular dis-ease. The hydrocarbon carotenoids,including
-carotene andlycopene,are transported primarily in LDL,which puts them inprime position to protect LDL from oxidation (29).Steinberg and Chait (30) found that supplementing smokers’diets with an antioxidant-rich tomato-based juice for 4 wk resulted in significantly increased conjugated diene (CD) lagtime,decreased CD propagation rate,and decreased breath pen-tane excretion compared with that in subjects given a placebo juice. Although it is impossible to separate the effects of lycopene from those of the other antioxidants added to the juice,the authors suggested that lycopene intakes correlated mostclosely with inhibition of LDL oxidation.In another intervention study,22 subjects (11 smokers,11 non-smokers) consumed a diet with increased fruit and vegetables,supplying
10 mg
-carotene,10 mg lycopene,and 10 mg luteindaily for 2 wk (28). The investigators observed an increase in CDlag time of 14% in smokers and 28% in nonsmokers after the sup-plementation. Again,these results cannot be attributed to lycopenealone,but they contribute to the evidence that carotenoids mayprotect against diseases related to oxidative stress.Romanchik et al (31) isolated LDL samples from 5 personsand enriched them with
-carotene,lycopene,and lutein todetermine whether this would have an effect on LDL oxidation.On copper-mediated oxidation of the LDL,the carotenoids weredestroyed before substantial amounts of lipid peroxidation prod-ucts were formed,providing further evidence that these pigmentsmay be working as antioxidants. Although lycopene was themost rapidly destroyed of the carotenoids studied,only the LDLenriched with
-carotene exhibited increased CD lag time. In aseparate study of LDL from 11 different persons,the sameresearchers actually found increased oxidation of LDL (as meas-ured by the ferrous oxidation–xylenol orange assay) on enrich-ment with lycopene and lutein,indicating that the relationbetween lycopene and LDL oxidation is complex (32).An intriguing nonantioxidant function of lycopene was shown invitro and in humans. Fuhrman et al (33) showed that the addition of lycopene to macrophage cell lines decreased cholesterol synthesisand increased LDL receptors. Incubation with lycopene in vitroresulted in a 73% decrease in cholesterol synthesis,which wasgreater than that achieved with
-carotene. Also,lycopene resultedin a 34% increase in LDL degradation in the cells themselves andapproximately a 110% increase in the removal of LDL from the cir-culation. To test their finding in humans,the investigators fed 6 men60 mg lycopene/d for 3 mo (approximately equivalent to the amountof lycopene in 1 kg tomatoes). They found a 14% reduction inplasma LDL cholesterol with no significant change in HDL choles-terol. Based on the calculations of Peto et al (34) that there is a 3:1ratio between lowering of cholesterol and reduction in the risk of myocardial infarction,we would expect an
30–40% reduction inrisk in persons consuming this amount of lycopene regularly.
EPIDEMIOLOGIC EVIDENCE FOR A PROTECTIVEEFFECT OF LYCOPENE ON RISK OF HEART DISEASE
The relation between
-carotene and cardiovascular diseasehas been examined in several studies,including clinical trialsinvolving
-carotene supplements,but in only a few has theassociation between lycopene intake or biomarkers and risk of this disease been examined (35). The study design and results of the 2 studies in which the association between circulating con-centrations of carotenoids and risk of heart disease were exam-ined are summarized in
Table2
. In addition,the table includesthe same information from the 2 other studies in which adiposetissue samples from the European Study of Antioxidants,Myocardial Infarction,and Cancer of the Breast (EURAMIC)were used to examine the relation between tissue concentrationsof lycopene and myocardial infarction.In 1994,Street et al (36) conducted a nested case-controlstudy examining serum carotenoid concentrations that weremeasured 7–14 y before the onset of myocardial infarction.Although there appeared to be an increased risk of myocardialinfarction in the lowest quintile of serum lycopene concentra-tion,there was not a dose-response relation and the trend was notstatistically significant. Serum
-carotene concentrations,how-ever,were significantly and inversely associated with risk of myocardial infarction. After stratifying the results by smoking,the authors found that this relation was limited to smokers only.The Atherosclerosis Risk in Communities study measuredcarotid intima-media thickness (IMT) as an indication of asymp-tomatic early atherosclerosis in 231 subjects,and 3 y later meas-ured serum antioxidant concentrations in the same persons (37).Although the relation was not significant,persons with higherserum lycopene concentrations had decreased odds of being inthe 90th percentile of IMT.
-Cryptoxanthin and lutein pluszeaxanthin were the only carotenoids that had a significantinverse association with carotid IMT.Using data from the Malaga center of the EURAMIC study of antioxidant concentrations in adipose tissue and incidentmyocardial infarction,Gomez-Aracena et al (38) found that therisk of myocardial infarction was 60% lower (odds ratio:0.39,95% CI:0.13,1.19;
P
for trend:0.04) for the highest quintile of adipose lycopene concentration than for the lowest quintile afteradjustment for age,family history of coronary heart disease,and cigarette smoking. The results of the total multicenter,multinational EURAMIC data set confirmed this effect. Menwith the highest concentrations of lycopene in their adipose tis-sue biopsy had a 48% reduction in risk of myocardial infarctionwhen they were compared with men with the lowest adiposelycopene concentrations (39). For each quintile increase inlycopene concentration,there was a significant decrease inmyocardial infarction risk. This association was partiallyLYCOPENE AND CARDIOVASCULAR DISEASE1693S
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