Lead Review Article
Lycopene: Chemistry, Biology, and Implications for Human
Health and Disease
Steven K. Clinton, M.D., Ph.D.
A diet rich in carotenoid-containing foods is asso-
ciated with a number of health benefits. Lycopene
provides the familiar red color to tomato products
and is one of the major carotenoids in the diet of
North Americans and Europeans. Interest in lyco-
pene is growing rapidly following the recent publi-
cation of epidemiologic studies implicating lyco-
pene in the prevention of cardiovascular disease
and cancers of the prostate or gastrointestinal
tract. Lycopene has unique structural and chemi-
cal features that may contribute to specific bio-
logical properties. Data concerning lycopene
bioavailabiliv, tissue distribution, metabolism, ex-
cretion, and biological actions in experimental
animals and humans are beginning to accumu-
late although much additional research is neces-
sary This review will summarize our knowledge in
these areas as well as the associations between
lycopene consumption and human health.
Introduction
Carotenoids are natural pigments synthesized by plants
and microorganisms.They provide considerable color to
our environmentand range from the elegant fall display in
New England forests, to the vibrant palette of flowers and
vegetables, to the subtle hues deposited in flamingo feath-
ers and lobster shells.’The best-characterizednatural func-
tions of carotenoids are to serve as light-absorbing pig-
ments during photosynthesis and protection of cells
against photosensitization.*Carotenoids provide protec-
tive coloration and identification for many species of in-
sects, crustaceans, and birds. Some dietary carotenoids,
such as p-carotene, serve as an important source of vita-
min A. However, the majority of carotenoids, including
lycopene, are devoid of provitamin A activity and their
poorly understood biological effects in humans must be
attributed to other mechanisms of action. Interest in caro-
~~
Dr. Clinton is clinical associate with the Dana-
Farber Cancer Institute, Harvard Medical School,
Boston, MA 02115, USA.
Nutrition Reviews, Vol. 56, No. 2
February 1998: (1)35-51
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tenoids, particularly lycopene, has grown rapidly owing
to studies suggesting a role in human health and disea~e.’?~
Chemistry
The structure of each carotenoid determines the color and
photochemical properties of the m ~ l e c u l eThe
. ~ structure
also contributes to the chemical reactivity of carotenoids
toward oxidizing agents or free radicals, which may be
relevant to in vivo processes in animals consuming di-
etary carotenoid~.~ More than 600 carotenoids, exclusive
of cis-trans isomers, have been characterized and share
common structural features, such as the polyisoprenoid
structure and a series of centrally located conjugated
double bonds.’,5p-Carotene is present in many foods and
is the major dietary carotenoid exhibiting the capacity to
undergo metabolism to vitamin A and metabolites (Figure
1). Lycopene is an acyclic carotenoid with 11 linearly ar-
ranged conjugated double bonds and found in relatively
few foods. Lycopene lacks the p-ionone ring structure
and is therefore devoid of provitamin A activity. The other
major classes of dietary carotenoids are the more polar
oxycarotenoids or xanthophils, such as lutein, P-cryptox-
anthin, and canthaxanthin (Figure 1).
Carotenoids are rich in conjugated double bonds, each
of which can theoretically undergo isomerization to pro-
duce an array of mono- or poly-cis isomers (Figure 1).
Interconversion is thought to occur with the absorption
of light, exposure to thermoenergy, or by participation in
specific chemical reactions. In most foods, lycopene and
other carotenoids typically occur in the all-trans configu-
ration, which is the most thermodynamically stable form.
Very little is understood about specific roles of cis or trans
isomers in vertebrate biology.
The structureof a carotenoid is a key determinantof the
physical properties, chemical reactivity, and biologic func-
tions or actions observed. Upon biosynthesis by plants and
microorganisms, each carotenoid is incorporated into very
precise orientations within subcellularstructuresof the pho-
tosynthetic a~paratus.2,~ The chemical and physical proper-
ties of the carotenoid are strongly influenced by other mol-
ecules within the microenvironment,particularlyassociated
proteins and membrane lipids. In turn, carotenoids can also
35
 9 4 s p-Carotene

All-trans &Carotene

All-trans p-Cryptoxanthin
0
All-trans Lycopene II

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HO All-trans Lutein 0 All-trans Canthaxanthin

Figure 1. Chemical sturctures of retinol and representative dietary carotenoids.

influence the properties of the subcellular structures. The stable during food processing and cooking.8,‘0Investiga-
unique chemical features of each carotenoid, such as size, tors interested in potential health-promoting effects of
shape, hydrophobicity, and polarity, determine its ability to tomato products must recognize that other carotenoids
incorporate correctly into the molecular environment and are present in tomato products and that their proportions
function within an appropriatecontext for any plant, bacte- tend to remain stable during food processing (Figure 2).
ria, or fhgus. Basedupon this knowledge, it is reasonable to Epidemiologistsand clinical investigators require stan-
postulate that when carotenoidsare consumed by mammals, dardized databases for translation of food intake data into
these same structuralproperties may dramaticallyinfluence quantitative estimates of lycopene consumption. Values
bioavailability,absorption,circulation,distributionto tissues, for the carotenoid content of foods have recently been
and ability to incorporate into subcellular components and published and employed in numerous studies.’J1J2The
affect very precise molecular processes. The unique struc- effects of using different sources of carotenoid data for
tural features of each carotenoid may be critically important
in the very specific, although largely poorly characterized,
effects of carotenoids on human health and disease pro- Table 1. Approximate Lycopene Content of Various
cesses. Lycopene, by virtue of its acyclic structure, large Foods Based on Analysis by a Variety of Laborato-
array of unconjugated double bonds, and extreme hydro- ries (mg/lOO g wet
phobicity, will undoubtedly exhibitmany unique and distin- Food Content (md100 g)
guishingbiologic featuresin mammalian systems.
Tomatoes, fresh 0.8W.20
Tomatoes, cooked 3.70
Sources of Dietary Lycopene and Estimationof Tomato sauce 6.20
Intake Tomato paste 5.40-1 50.00
Tomato soup, condensed 7.99
Dietary lycopene is derived from a limited list of foods Tomato powder, drum or
(Table lC9), in contrast to the other major carotenoids spray dried 112.6S126.49
consumed by humans and found in a diverse array of Tomatojuice 5.00-1 1.60
Sun-dried tomato in oil 46.50
fruits and vegetables. More than 80% of lycopene con- Pizza sauce, canned 12.71
sumed in the United States is derived from tomato Ketchup 9.9G13.44
(Solanum lycopersicum) products, although apricots, Apricot co.01
guava, watermelon, papaya, and pink grapefruit also con- Apricot, canned 0.06
Apricot, dried 0.86
tribute to dietary intake.@ The lycopene content of toma- Grapefruit,raw pink 3.36
toes can vary significantly with ripening and in different Guava, fresh 5.40
varieties of tomatoes. Lycopene concentrations in the very Guavajuice 3.34
red strains approach 50 mglkg compared with only 5 mg/ Watermelon, fresh 2.30-7.20
Papaya. fresh 2.W5.30
kg in yellow varieties.6Lycopene appears to be relatively

36 Nutrition Reviews, Vol. 56, No.

 lycopene 811 neurosporene p-carotene; much less is known about other carotenoids.
-Lh- (7-9%)
Carotenoids are tightly bound to macromolecules in most
foods, and absorption therefore may be problematic.2'
Many factors influence initial carotenoid release from the
physical matrix of food and dissolution into lipid droplets
within the stomach and duodenum.20Heating foods prior
to ingestion can improve carotenoid bioavailability as a
0 &carotene result of the dissociation of the protein-carotenoid com-
(1-2%) plexes or dispersion of crystalline carotenoid aggregates.
ycarotene Lipids play an important role in carotenoid dissolution
(10-1 1%)

-
and subsequent absorption. For example, lycopene is more
E l &carotene efficiently absorbed when tomato juice is warmed with
:.:.:.:.:I
....
.....
..........
..... (14%)

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......... supplemental lipid.22As a result of the action of bile salts
rn lutein and pancreatic lipases, carotenoid-containing lipid drop-
(trace-1 %)
lets enter the duodenum and form multilammellar lipid
Figure 2. Carotenoid profile of tomato products vesicles.18 The transfer of carotenoids from the micelle
into the mucosal cells appears to take place via passive
diffi~sion.~~,~~
epidemiologic studies of lycopene intake or studies of
The ability of micelles to incorporate carotenoids may
diethenun lycopene relationships were recently evalu-
depend on the dietary fatty acid patterns and structural
ated.I3A 100-item food frequency questionnairewas com-
features of the carotenoid.I8Lipid malabsorption, owing
pleted and lycopene intake was estimated using the U.S.
either to disease processes or to drugs, may inhibit up-
Department of Agriculture-National Cancer Institute
take. Nonabsorbable lipids, such as sucrose polyesters
(USDA-NCI) carotenoid food composition database in
that are currently entering the food supply as fat substi-
comparison with the database accompanying the Block-
tutes, may serve as a hydrophobic sink in the intestinal
NCI Health Habits and History Questionnaire (HHHQ).
lumen and reduce carotenoid absorption. Indeed, studies
Estimated lycopene intake of 593 versus 1615 mg/day was
of daily olestra consumption (18 g/day) show a signifi-
observed for the HHHQ versus the USDA-NCI databases,
cant reduction in serum lycopene concentrations in the
respectively. Despite these enormous quantitative differ-
range of 30% after 16 weeks.25The olestra-induced malab-
ences in estimated intakes, the two databases similarly
sorption of lycopene is greater than for less lipophilic
ranked individuals according to carotenoid intake, with a
hyroxylated carotenoids, such as P-cryptoxanthin, zeax-
Spearman correlation coefficient of 0.7 1. Differences be-
anthin, and l ~ t e i nThe
.~~observed reduction in serum caro-
tween estimated dietary lycopene and serum lycopene
tenoid concentrations in those consuming olestra at this
correlations for the two databases were minor. Interest-
relatively high dose is similar to that reported for high
ingly, the relationship between estimated intake and se-
fiber diets.26The possibility that fat substitutes will sig-
rum lycopene is very poor, with ~ 0 . 2 or 9 0.25, confirming
nificantly impact carotenoid absorption under conditions
previous studies reporting correlations of 0.1-0.34 in dif-
of usual consumption remains to be d e t e ~ m i n e d . ~ ~ ? ~ ~
ferent populations.l"I7 Although estimates of lycopene
Chylomicrons are responsible for carrying caro-
intake differed enormously depending on the assessment
tenoids from the intestinal mucosa to the blood stream via
tools employed, the minor differences in carotenoid
the lymphatics.18Carotenoidsare transported in the plasma
rankings and diet-serum correlations suggest that the cur-
exclusively by lipoproteins, and no other carotenoid-spe-
rent tools can differentiate subgroups based on relative
cific binding or carrier proteins have been identified.18,28
lycopene intake. Improvements in the estimation of lyco-
The physical properties defined by carotenoid structure
pene intake in free-living populations are clearly needed
appear to contribute to the varying distribution of spe-
to provide quantitative data that can be compared across
cific carotenoids among lipoprotein classes. It is hypoth-
epidemiologic studies and provide the foundation for the
esized that very lipophilic carotenoids, such as lycopene,
design of clinical and laboratory studies.
are found within the hydrophobic core of the lipoprotein
particle, whereas carotenoids with polar functional groups
Kinetics of Lycopene Absorption, Transport, and
may extend at least partly to the aqueous interface at the
Metabolism
surface. This orientation may in turn influence the uptake
Carotenoids exhibiting distinct structural and physical by extrahepatic tissues. The bulk of lycopene and a-and
properties will undoubtedly exhibit differences in the dy- p-carotene is transported in LDL in contrast to the oxy-
namics of absorption, distribution, metabolism, and excre- genated carotenoids (lutein, zeaxanthin, canthaxanthin,
tion.ia20Most of our knowledge is derived from studies of and P-cryptoxanthin), which are more equally distributed

Nutrition Reviews, Vol. 56,No. 2 37

between LDL and HDL.29The content of carotenoids and
vitamin E in small, dense LDL is diminished compared to
normal LDL.29The authors conclude that the diminished
contents of these carotenoids and vitamin E could under-
lie the lower oxidative resistance of small, dense LDL and
also reduced tissue targeting of these antioxidants in sub-
jects having a dense LDL phenotype.
Another key unresolved issue is whether the HDL
carotenoids participate in some type of reverse transport
from extrahepatic tissues to the liver, as has been pro-
posed for cholesterol. Additional efforts to define how
lipoprotein profiles influence the tissue distribution of ly-
copene as well as its isomers and metabolites are needed.
Mean serum concentrations of lycopene in different
populations range from 50 to 900 nM/L, although
interindividual variation is typically very large, with stan-
dard deviations usually in the range of 50% of the mean or
more.4J5J6.3G36 Mean serum lycopene concentrations in
different populations around the world generally reflect
the consumption of tomato products. For example, in Cen-
tral America, Japan, and Senegal, serum concentrations in
children ranged from 70 to 120, whereas children in the
United States have a much higher mean concentration
(800 n w ) . Few studies have examined concordancecor-
relation coefficients for serum lycopene over time. In one
study, fasting lycopene concentrations determined 2
weeks apart in children were found to exhibit a correlation
coefficient of 0.89,37supporting other studies that sug-
gest that lycopene concentrations fluctuate modestly ex-
cept when significant changes in intake occur. Lycopene
does appear to be relatively stable in blood samples col-
lected using standard clinical techniques and stored at
-70 "C over several year^.^^.^^
Several studies have examined changes in serum ly-
copene that occur after changes in dietary intake have
been instituted. Restriction of dietary sources of lyco-
pene results in a gradual decline in plasma lycopene con-
centration. For example, in studies of healthy individuals
consuming a low-carotenoid diet, the plasma depletion
half-life of lycopene was estimated to be between 12 and
33 days, compared with less than 12 days for P - ~ a r o t e n e . ~ ~ dysfunction can alter carotenoid tat us.'^^^^^^^ Studies in
In several studies, supplementing a diet with foods con-
taining lycopene will very gradually restore total plasma
concentration^.^'.^^ One 6-week study of volunteers fed
180 mg tomato juice that contained 12 mg lycopene re-
ported that serum concentrations increased by only 34
~IM/L.~I Lycopene bioavailability was recently evaluated
following a single dose of fresh tomatoes or tomato paste
by analyzing carotenoid concentrations in the chylomi-
cron fraction of the systemic ci r ~ u l a t i o nEach
. ~ ~ source of
lycopene (23 mg) was provided together with 15 g corn
oil. Tomato paste was found to yield a 2.5-fold greater
total and all-trans lycopene peak concentration and a 3.8-
fold greater area under the curve than fresh tomatoes. The
area under the curve for cis isomers was significantly higher
38
after ingestion of tomato paste than fresh tomatoes. These
observations support the concept that food processing
and cooking can enhance the bioavailability of caro-
t e n o i d ~ . ~A~ single
. ~ ' , ~ingestion
~ of tomato soup that con-
tains 186 mmol lycopene demonstrated a minimal change
in serum lycopene ~oncentration.4~ Yeum et a1.44examined
the plasma carotenoidresponse after changing from a self-
selected New England diet to a diet rich in fruits and veg-
etables containing approximately 16 mg/day carotenoids
and 3.3 mg/day lycopene. Cis and trans isomers of lyco-
pene were all significantly increased in the high fruit and
vegetable diet over 1-2 weeks. In general, total serum ly-
copene changes gradually with alterations in dietary in-
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take; chylomicron lycopene content is a better approach
for assessing recent meals.
Several biologic and lifestyle variables appear to be
associated with changes in serum lycopene concentra-
tions. Investigators should recognize, however, that the
associations may reflect the influence of a specific behav-
ior or physiologic factor on carotenoid intake.16Aging is
correlated with a gradual decline in serum concentrations
of lycopene.16*34 Although not consistently o b ~ e r v e d , ' ~ - ~ ~
inverse correlations between greater body mass and lyco-
pene plasma values have been Blood lycopene
concentrations are not significantlydifferent between men
and women in most s t u d i e ~ . ' A ~ ,recent
~ ~ , ~study
~ showed
that lycopene concentrations peak in the middle of the
luteal phase of the menstrual cycle in nonsmoking women
who consumed a standard diet with 10 mg total caro-
tenoids for two cycles under isoenergetic condition^.^^
The cycle fluctuation could influence the estimation of
plasma carotenoid-disease relationships in studies of pre-
menopausal women, and should be considered. Some stud-
ies have suggested that lycopene concentrations may be
lower in smokers compared with nonsmoker^,'^ whereas
others report no effect of The exposure
of freshly obtained human plasma to the gas phase of
cigarette smoke led to the depletion of many lipophilic
antioxidants, with lycopene being the most sensitive to
d e g r a d a ti~ nAlcohol
.~~ consumption and associated liver
patients with alcoholic cirrhosis, as well as more modest
liver disease, show that these patients have significantly
reduced concentrations of hepatic lycopene, although
their serum concentrations are less consistently altered.52
A recent study was completed in healthy individuals who
consumed alcohol (30 g/day) in a controlled fashion for 3
months. The study showed that serum concentrations of
a-and p-carotene increased, whereas concentrations of
lutein and zeaxanthin were decreased and lycopene con-
centrations were not affected.48
Very little is known about the metabolism or degrada-
tion of lycopene in r n a m m a l ~ .Few
~ . ~ metabolites of lyco-
pene have been documented in human plasma or tissues.
For example, 5,6-dihydroxy-5,6-dihyro-lycopene has been
Nutrition Reviews, Vol. 56,No. 2
detected by Khachik et al.53It is postulated that this com-
pound may be a product of an in vivo oxidation reaction
via an intermediate lycopene epoxide. Additional efforts
are necessary in the area of analytic techniques to estab-
lish the tools necessary to examine the small quantities of
lycopene metabolites present in blood or tissues.
Lycopene Distribution to Tissues, Milk, and
Seminal Fluid
Although data are still limited, it is clear that carotenoids
are not uniformly and equally distributed in tissues. The
tissue-specific carotenoid patterns reported thus far sug-
gest a mechanism whereby certain carotenoids may exert
unique biologic effects in one tissue but not in another.
For example, the xanthophylls lutein and zeaxanthin are
virtually the only carotenoids occurring in the macula of
the human retina, suggesting a role in normal retinal biol-
ogy and disease p r o c e ~ s e s .The
~ ~ *available
~~ data from
samples obtained in Western cultures suggest that lyco-
pene is a prominent carotenoid in the adrenal glands, tes-
tes, liver, and prostate (Table 2).30,5M1 The processes that
underlie these patterns, particularly the very high con-
centrations in the adrenals and testes, remain speculative.
In all reported studies, the between-person variation for
tissue concentrations of lycopene or other carotenoids
are very high (30- to 100-fold).
Adipose tissue is a potential source of readily acces-
sible biologic material for the assessment of body lyco-
pene status and may serve as a marker of internal dose,
taking into account the variations in consumption, ab-
sorption, and metabolism. However, studies have not yet
been completed to determine how well adipose tissue caro-
tenoid patterns reflect the concentrations in other tissues.
A large study was recently completed in eight European
nations and Israel to evaluate adipose tissue carotenoid
patterns in more than 600 male and female Over-
all, adipose tissue carotenoid levels were lower in men by
21-50% compared with women. Body mass index and waist
circumference were all inversely related to adipose tissue
Table 2. Tissue Concentrations of Lycopene in Human Samples (nM/g)*
Tissue Stahl et a1.3’ KaDlan et a1.56
Testis 4.3 (0.4-9.4) 21.4
Adrenal 1.9(0.2-5.6) 21.6
Liver 1.3 (0.1-4.1) 2.5
Prostate
Adipose 0.2 ( ( M . 5 ) 13
Breast
Pancreas 0.7
Lung
Qdney 0.2 (0.14.3) 0.4
Ovary 0.3 (0.14.4) 0.3
Stomach
~~
*Data are derived from laboratories using different analytical technology and samples from individuals of different ages, sex, and state
of health. Data represent means or median values with range if provided by the authors.
Nutrition Reviews, Vol. 56, No. 2
lycopene content. Another study examined breast adi-
pose tissue carotenoid concentrations and found mean
concentrations in the range of 0.2-1.3 mglg dry fat but no
significant correlation with estimated intake based upon a
food frequency questionnaire (FFQ).‘j3Future clinical and
epidemiologic studies that employ adipose tissue lyco-
pene content as a biomarker must also consider gender,
body s u e and composition, smoking, and alcohol intake
as potential confounders of a lycopene-disease relation-
ship.
The relationships among estimated lycopene intake,
serum lycopene, and tissue lycopene concentrations have
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rarely been i n ~ e s t i g a t e d .One
~ ~ . ~study
~ evaluated paired
plasma and skin concentrations of lycopene and other
major carotenoids and reported correlation coefficients of
0.61 or 0.76.65Similarly,lycopene in plasma correlatedvery
well with the lycopene in gastric biopsies, with a regres-
sion coefficient of 0.77.60Breast adipose tissue lycopene
was found to be unrelated to estimated intake by FFQ and
showed a correlation coefficient of only 0.17 in a group of
48 women.63
Lycopene and other dietary carotenoids are found in
human milk at concentrations of approximately 10% of
those in ~ e r u m . ~An~ .in-depth
~’ analytic effort by Khachik
et al.53described 34 carotenoids, including 13 geometrical
isomers and 8 metabolites, in the breast milk and Serum of
lactating women. Among the compounds identified were
two oxidation products of lycopene. The oxidative me-
tabolites of lycopene with a novel five-member ring and
end group have been identified as epimeric 2,6-
cyclolycopene- 1,5-diols. Future efforts are necessary to
determine the relationships among intake of lycopene,
concentrations in human milk, and transfer to the infant.
Seminalplasma from normal and immunoinfertilemen
(those having antisperm antibody titers) were recently
evaluated.68The levels of p-carotene, lycopene, and ret-
inol were significantly decreased in immunoinfertile men
compared with those in fertile men. This is the first report
of carotenoids in local genital tract secretions of men. The
Nierenberg et a1?*
Clinton et al.59
Schmitz et al.5’ Sanderson et a1.6’
5.4 (0-20.7)
0.8 (0-1.7)
0.8
0.6 (0.14.2) 0.2
0.6 (0.1-2.4)
0.2
39
possibility that dietary carotenoids and other antioxidant
compounds may play a role in male reproduction and fer-
tility will be investigated in future studies.
Overall, it appears that lycopene concentrations in
blood, secretions, and tissues are defined by many inter-
acting variables, including seasonal dietary composition,
food preparation practices, meal composition, factors af-
fecting lipid absorption,lipoproteinmetabolism,and poorly
understood mechanisms controlling tissue uptake and me-
tabolism.
InteractionsBetween Lycopene and Other
Carotenoids
It has been hypothesized that high intake of some caro-
tenoids may influence or antagonize the bioavailability
and absorption of other carotenoids. For example, lyco-
pene and canthaxanthin are reported to exhibit antago-
nism for absorption and distribution to the liver.69Studies
of p-carotene supplementation for 1 month have revealed
reduced concentrations of lipoprotein lycopene concen-
trations in parallel with increased lipoprotein P-~arotene.~~ Many of the putative biologic effects and health benefits
In contrast, volunteers fed various concentrations of a
lycopene-enriched lipid extract of tomatoes were found to
have no changes in concentrations of other car~tenoids.~' radicals are defined as molecules that have unpaired or
Quite different results were observed in a long-term study
of p-carotene supplementation (20 mg/day) for 2 years in
the Australian polyp prevention project. An increase in
serum lycopene concentration of approximately 175%was
observed in those supplemented with p-carotene com-
pared with pla~ebo.'~ A study of older women receiving
90 mg p-carotene compared with placebo reported a 14-
fold increase in plasma p-carotene but no effect on lyco-
~ e n eNierenberg
.~~ et al.58found that patients receiving 25
mg P-carotene/day for 4 years in a colon polyp prevention
trial showed only a 5% increase in lycopene. Although
competition between lycopene and other carotenoids for
processes related to absorption, distribution, and biologic
functions remains a theoretical possibility, definitive data
remain to be generated.
cis-trans lsomerizationin Food Products and In
Vivo
New analytic techniques have allowed investigators to
detect and quantitate lycopene isomers in foods and bio-
logic samples.44,59.77,75 Small amounts of cis isomers have
been detected in tomatoes or processed tomato products,59
whereas much greater concentrations appear to be found
in human blood and t i s s ~ e s . ~ ~ , ~ ~Furthermore,
+ ' , ~ ~ . ~ ~ we ionizing radiation, sunlight, heat shock, and air pollutant:
have observed that the patterns of isomers observed in
human samples are qualitatively similar to those derived
from mice fed diets containing tomato products or lyco-
pene beadlets (unpublished data). We typically observe
12-1 3 different lycopene isomers in human serum samples
and 14-18 different isomers in prostate tissue.59We can
40
estimate from the few available studies that the propor-
tion of blood lycopene in various cis forms averages ap-
proximately 50%, compared with less than %lo% in
food^.^,",^^ An even greater proportion, approximately
80%, of total lycopene is found as cis isomers in prostate
tissue.59
At this time, the biologic relevance of cis isomers is
unknown. cis Isomers differ significantly in molecular
shape from the all-trans form. It can be hypothesized that
the ability of cis isomers to incorporate into lipoproteins
or subcellular lipid structures as well as interact with vari-
ous proteins will be changed significantly. cis Isomers are
also less likely to crystallize or aggregate and may there-
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fore be more efficiently solubilized in lipophilic solutions
and more readily transported within cells or between tis-
sues. The possibility that cis-isomer patterns may reflect
the participation of lycopene in specific biologic reactions
remains to be determined.
Quenching of Reactive Oxygen by Lycopene
of lycopene and other carotenoids are hypothesized to
occur via protection against oxidative damage.3~4,77~78 Free
odd numbers of electrons in the outer orbital. The addi-
tion of a single electron to 0, produces the superoxide
radical 0;. The addition of another electron and two hy-
drogen ions yields hydrogen peroxide (H,02),which upon
combining with O;, produces hydroxyl radicals OH. The
hydroxy radical rapidly interacts with macromolecules in
the immediate environment and can produce enormous
damage to proteins, lipids, and DNA. Polyunsaturated
fatty acids are particularly opportune targets of free radi-
cals, and chain reactions generate a cascade of reactive
intermediates.Although not technically a free radical, sin-
glet oxygen (lo2) is also a very reactive high-energy and
short-lived oxygen species formed in biologic systems
that can react with biomolecules. Several sources of en-
dogenous oxidants have been characteri~ed.~~ The leak-
age of partially reduced oxygen molecules during normal
aerobic respiration is unavoidable. Immune-competent
cells release nitric oxide (NO) and various oxygen radicals
during acute and chronic immune responses. Peroxisomes
involved in fatty acid metabolism and the cytochrome P-
450 microsomal electron transport chain are additional
sources of reactive oxygen. Exogenous sources include
some drugs and environmental toxins, cigarette smoke
such as nitrogen dioxide and ozone.79
Mammals have developed a number of defense:
against reactive oxygen, some of which are geneticall:
programmed, such as the enzymes superoxide dismutasl
and glutathione peroxidase, and others that are derive!
from nutritional substances such as vitamin E, vitamin C
Nutrition Reviews, Vol. 56, No.
selenium, and perhaps carotenoids.80The ability of lyco-
pene to quench lo, or oxygen radicals is only beginning
to be investigated in experimental systems. The quench-
ing of IO, by lycopene and other carotenoids can occur
through physical or chemical means. Physical quenching
predominates and leaves the carotenoid intact, whereas
chemical quenching is responsible for the decomposition
of the carotenoid (“bleaching”). Physical quenching in-
volves the transfer of excitation energy from lo, to the
carotenoid, thereby producing ground-state oxygen and
a carotenoid in the excited triplet state. The excess energy
is dissipated as heat through rotational and vibrational
interactions with the surrounding solvent and structures.
The regeneration of the ground-state carotenoid allows it
to function as a catalyst and undergo additional cycles of
IO, quenching. The quenching capacity of carotenoid
depends primarily on the number of conjugated double
bonds, which accounts for the exceptionally high capac-
ity exhibited by lycopene compared with many other caro-
t e n o i d ~ .Lycopene
~ ~ , ~ ~ may
~ ~ also interact with reactive
oxygen species such as hydrogen peroxide and nitrogen
dioxide.8e6 A recent study showed that lycopene was
exceptionally potent and twice as effective as p-carotene
in protecting lymphocytesfrom NO, radical cell death and
membrane damage.84,87 p-carotene is an efficient scaven-
ger of peroxyl radicals, especially at low oxygen tension.88
Although less research has focused on lycopene, current
studies suggest that lycopene is a more potent scavenger
of oxygen radicals than other major dietary c a r ~ t e n o i d s . ~ ~ tional intervention trials are now under way.
It is very important that investigators begin to evalu-
ate the hypothesized antioxidant effects of lycopene in
vivo and how lycopenemay interact within the network of
host and other dietary defenses against oxidative dam-
age. For example, lycopene is extremely hydrophobic and
is most commonly located within cell membranes. There-
fore, the reactions of lycopene with reactive oxygen mol-
ecules may be limited to the hydrophobic inner core of the
membrane unless the lycopene is associated with specific
proteins extending to the membrane surface and interact-
ing with the aqueous environment. As predicted, the free
radicalscavenging abilities of lycopene are more profound
in a lipophilic envir~nment.~~ These observations have
implications for how lycopene may protect against very
specific types of oxidative damage in subcellular loca-
tions and complement other defense systems.
The participation of lycopene in reactions with free
radicals is probably intimately linked with lycopene deg-
radation pathways and will ultimately define the biologic
lifetime of lycopene in vivo. In carefully controlled solu-
tions, lycopene was found to react more rapidly with oxi-
dizing agents than were other carotenoids tested, result-
ing in rapid bleaching owing to disruption and breakdown
of the primary structure.86It is very difficult to investigate
the degradation of lycopene in vivo, owing to the very
Nutrition Reviews, Vol. 56,No. 2
short-lived nature of the intermediate compounds and the
very low concentrations of end products formed. The
quenching of free radicals may involve apocarotenals or
apocarotenonesas well as epoxides. It is not know whether
stable-chain-breaking lycopene radicals or prooxidant
peroxyl radicals are formed during this process in vivo.
Tomatoes, Lycopene, and Cancer Risk
A rapidly accumulatingand overwhelmingamount of evi-
dence from various epidemiologicstudies around the world
suggests that a diet containing a diverse array of fruits
and vegetables results in a lower risk for several types of
c a n ~ e r .These
~ ~ ? ~observations
~ led some investigators to
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postulate that carotenoids, particularly p-carotene, may
be the critical protective factor in these diets.93This hy-
pothesis was reinforced by rodent experiments and stud-
ies showing that higher blood concentrations of p-caro-
tene were correlated with lower risk of several cancers,
particularly tobacco-related m a l i g n a n c i e ~ .Several
~ ~ - ~ ~in-
tervention trials using p-carotene in pure form were un-
dertaken to test the hypothesis, with some interesting and
startling results. No effects of p-carotene were noted on
skin colon adenoma~?~ or overall cancer
whereas two large, randomized, placebo-controlled trials
in high-risk populations showed an increased rate of lung
cancer in supplemented g r o u p ~ . In ~~ contrast,
J ~ ~ a protec-
tive effect against oral leuk~plakia’~l-’~~ and premalignant
lesions of the cervixlo6have been suggested, and addi-
The results of these studies show that the simple
extrapolation from fruit and vegetable intake to
chemopreventionby a pure carotenoid will not be a pana-
cea for the cancer problem. Fruits and vegetables contain
a myriad of chemical substances, some of which are nutri-
ents and others of which have potent biologic activities
but are not nutrients by traditional classification. People
who consume diets rich in fruits and vegetables often
also consume more fiber, less fat, less refined carbohy-
drate and demonstrate other health-conscious lifestyle
behaviors. As we investigate the possible role of lyco-
pene as a cancer preventive agent we should consider the
lessons learned over the last decade from studies of p-
carotene. It is abundantly clear that the basic science con-
cerning lycopene, ranging from food processing, nutrient
bioavailability, absorption, in vivo metabolism, tissue dis-
tribution, and biomarkers of activity, remains poorly un-
derstood and must be very carefully examined in conjunc-
tion with efforts to move rapidly toward evidence-based
intervention studies.
Cell culture systems provide the opportunity to in-
vestigate molecular and biochemical roles for lycopene in
normal and malignant cells. However, the possibility of
detecting effects that are artifacts of experimental tech-
niques and not relevant to in vivo phenomena is very
41
high for substances such as lycopene. Preliminary stud-
ies suggest that carotenoids are unstable when provided
to cells in typical oxygen-rich, warm environments over
several days.Io7Carotenoids can be incorporated into cell
culture media by several methods, such as solubilization
in organic solvents, water-soluble beadlets, artificial lipo-
somes, or enriched bovine serum. Each of these ap-
proaches provides differing stability and uptake of caro-
tenoids by the cells in culture. It is imperative that inves-
tigators working with carotenoids in cell culture incorpo-
rate HPLC analysis of carotenoid stability, cellular con-
centrations, and metabolism into their investigations in
order to interpret the data obtained and adequately as-
sess important hypotheses. Very little work has thus far
been completed with lycopene in cell c ~ l t u r e Lycopene
.~,~
was found to protect cultured hepatocytes against car-
bon tetrachloride injury and death.lo8Several studies have
reported antiproliferative effects of lycopene against can-
cer cells in c u l t ~ r e . ~Chemical
* ~ J ~ ~ mutagenesis assays of
Salmonella typhimurium strains TAlOO and TA98 are used
as a screening test for putative carcinogens. Lycopene
was found to have minimal capacity to block aflatoxin B,-
induced DNA damage in this systern.l'O Bertram and col-
leagues have developed the hypothesis that carotenoids,
including lycopene, can inhibit the transformation of cul-
tured cells via the up-regulation of gapjunctional commu-
nication resulting from the increased expression of
connexin 43, a key protein forming the gap junction.l'1-1'4
Rodent models provide an excellent opportunity to
assess the anticancer properties of lycopene under con-
ditions of precise control of all other potentially confound-
ing dietary variables. Although hundreds of models of
experimental cancer are available, little is known about the
absorption and distribution of dietary lycopene in rodents
and its effects on tumorigenesis. Our preliminary studies
with lycopene from oleoresin, tomato powder, and other
vehicles suggest that lycopene is poorly absorbed by rats
and mice fed purified diets. However, concentrations of
lycopene in the rodent diet that are higher than those
found in human diets will allow enough absorption to
achieve concentrations in the tissues of rodents that are
similar to those reported for humans. To ensure lycopene
stability, diets must be prepared carefully with minimal
heat and light exposure. Furthermore, we recommend cold
storage and frequent replacement of food in cages to mini-
mize degradation prior to consumption. Careful monitor-
ing of food intake and body weight is critical in all rodent
nutrition and cancer studies, because energy intake is a
profound stimulus for tumor growth.'I5J6We recommend
that investigators evaluate their diets and quantitate the
actual concentration and the isomer pattern of lycopene
present after diet preparation. Furthermore, it is essential
to determine blood and tissue concentrations over time in
order to interpret study results and place data in perspec-
tive relative to the literature in humans. The inhibition of
42
brain and breast tumorigenesis in animal models has been
described in response to administration of lycopene.117-1'9
A provocative study of mice almost 40 years ago showed
that intraperitonealinjection of lycopene ameliorated tox-
icity from total body irradiation.120
Investigators must consider many direct effects of
lycopene on developing tumors as well as indirect effects
mediated through the host. For example, lycopene could
influence the cancer cascade by modulating hormone sta-
tus, carcinogen metabolism, immune status, and angio-
g e n e s i ~ . ~ , ~Very
J ~ ~little
- ' ~ effort
~ has focused thus far on
the ability of lycopene to modulate these processes in
humans or in animal models.
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Lycopene and Cancers of the Digestive Tract
Cancers of the esophagus, stomach, colon, and rectum
are major malignancies throughout the world, and each
exhibits unique etiologic features and biologic processes.
One of the first studies examining the role of lycopene-
containing foods in cancer risk was completed in northern
Iran, where esophageal cancer is exceptionally prevalent.
Weekly tomato consumption in a case-control study was
associated with a 40% reduction in risk.'25This relation-
ship also was observed in a case-control study in Italy.IZ6
Gastric cancer remains a major problem in many parts
of the world, and several studies have reported protective
effects for diets rich in tomato p r o d ~ c t s , ~ * "whereas
'~~
several others have reported no r e l a t i o n ~ h i p . lFor
~ ~ .ex-
~~~
ample, one case-control study in Italy suggested that lower
social class, higher salt intake, and alcohol consumption
enhanced risk, whereas greater intakes of fruit and veg-
etables, particularly tomatoes, appeared to be pr0te~tive.l~~
More recently, another Italian case-control study reported
that consumption of seven or more servings of tomato
products per week compared with less than two servings
per week was associated with a 50% reduction in risk.126 A
cross-sectional study in Japan confirmed that salt appeared
to be a positive risk factor, whereas assays of blood mi-
cronutrients, including vitamins A, C, and E and p-caro-
tene, were unrelated. Higher concentrations of serum ly-
copene, however, were associated with a reduced risk of
gastric cancer.130
Infection of the gastric mucosa with Helicobacter
pylori is associated with gastric ulcers and risk of cancer.
Infection results in an inflammatory response that is per-
haps associated with the release of reactive oxygen spe-
cies and genetic damage that may initiate or promote the
cancer cascade. Sanderson et a1.60found no difference in
the concentrations of gastric mucosal lycopene and a-or
p-carotene between H. pylori-positive and control
groups.
Pancreatic cancer is a disease of obscure etiology
and is particularly devastating owing to its insidious on-
set, diagnosis at late stages, and poor response to therapy.
A study of prospectively collected serum samples from a
Nutrition Reviews, Vol. 56, No. 2
cohort was employed to compare serum micronutrients
from those developing pancreatic cancer and matched
contr01s.l~~ The greatest difference between cases and
controls was observed for lycopene at 700 nM/L versus
930 nM/L, respectively. Because lycopene uptake and se-
rum concentrations may be related to the digestibility of
dietary lipids, diseases of the pancreas could significantly
reduce absorption and perhaps confound studies such as
these.
Cancers of the colon and rectum are associated with a
growing number of diet and nutrition f a c t o r ~ . Among ~~J~~
the factors examined, one of the most consistent associa-
tions is the reduced risk of colon and rectal cancer with
diets rich in vegetable^.^^ The intake of tomato products
was not associated with these malignancies or polyps in
some human s t u d i e ~ , ’but ~ ~several
J ~ ~ have reported in-
verse r e 1 a t i o n ~ h i p s . IA
~ ~recently
’ ~ ~ published large case-
control study from Italy shows an odds ratio (OR) of 0.49-
0.68 for subjects consuming tomato products daily com-
pared with those consuming less than two per week.126
Lycopene and tomato products have not been extensively
evaluated in rodent models of colon carcinogenesis. In
one study, lycopene was associated with a reduction in
the development of aberrant crypt foci of rats treated with
the carcinogen N-methyl-nitrosourea.139
Lycopene and Cancer of the Cervix
Cancer of the cervix is the second most common malig-
nancy in women worldwide, although rates are declining
in nations with active screening programs. The main etio-
logic factor is probably sexually transmitted infectious
agents, such as human papillomaviruses. A role for di-
etary factors in modulating the pathogenesis or incidence
of cervical cancer remains to be clearly e~tablished.~~
How-
ever, most epidemiologic studies have consistently ob-
served a lower risk associated with diets rich in fruits and
vegetable^.^^ Very few studies have specificallyexamined
the roles of tomato products or lycopene. Several case-
control studies of estimated lycopene intake or serum con-
centrations have not detected a significant relationship
with A recent case-control study compared
women with cervical intraepithelial neoplasia, a probable
premalignant marker for cervical cancer, with normal con-
trols and observed that lycopene was the only carotenoid
showing an inverse association with risk based on dietary
intake and serum concentration^.'^^
Lycopene and Breast Cancer
Overall, several case-control studies have not consistently
observed an inverse relationship between estimated lyco-
pene intake or serum lycopene concentrations and breast
cancer Furthermore, a recent study of dietary
intake interviews of 4697 women in Finland showed no
relationship between estimated intake of tomato products
and breast cancer risk.147
A recent case-control study con-
Nutrition Reviews, Vol. 56, No. 2
ducted in Boston examined the relationship between breast
adipose tissue lycopene concentrations and breast can-
cer risk.63An inverse association between lycopene and
breast cancer risk was observed (OR for above the mean
versus below the mean, 0.32,95% CI 0.1 14-94).The ef-
fects of lycopene on breast carcinogenesis using the 7,12-
dimethylbenz(a)anthracene(DMBA)-inducedrat mammary
cancer model were recently evaluated.IIs Rats were pro-
vided a lycopene-enriched tomato olioresin by intraperi-
toneal injection for 2 weeks prior to DMBA exposure and
continuing for an additional 16 weeks after carcinogen
administration. Those treated with a tomato olioresin de-
veloped fewer tumors and the tumor volume was smaller
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than in controls. In comparison, rats treated with p-caro-
tene showed no protection in this model. Another report
describes the inhibition of spontaneous mammary tumors
in SHN mice fed a lycopene-containingdiet.Il7A cell cul-
ture study reported that lycopene inhibited proliferation
of human MCF-7 mammary cancer cells.’09
Lycopene and Skin Cancer
There has been a great deal of interest in exploring the
relationshipbetween carotenoids, including lycopene, and
risk of skin cancer. Exposure of the skin to ultraviolet (UV)
radiation leads to bums, photosensitivity, premature ag-
ing, and increased risk of cancer. UV exposure is associ-
ated with the local production of singlet oxygen and free
radicals. The role of carotenoids in plants in quenching
UV-induced oxidative products has been proposed to be
analogous to human skin, because UV light acts as a pho-
tosensitizer, inducing the generation of free radicals, sin-
glet oxygen, and other reactive species. A recent study
observed that a controlled dose of solar-simulated light
resulted in a 3 1 4 6 % decrease in skin lycopene compared
with an adjacent nonexposed area in 16 women.‘48Inter-
estingly, no significant change in skin P-carotene was ob-
served. These observations are consistent with the hy-
pothesis that reduced concentrations of lycopene in
skin following UV irradiation may be an indication of its
role in defending against UV-induced reactive oxygen.
The possibility that diets low in tomato products and ly-
copene lead to low concentrations of lycopene in the se-
rum or skin and thus place individuals at greater risk of
sunlight-induced skin damage remains to be thoroughly
investigated.
Lycopene and Bladder Cancer Risk
Bladder cancer is a disease caused primarily by tobacco in
developed nations, whereas occupational exposures and
parasitic infections contribute to risk in some subgroups
and geographic areas. The consumption of diets rich in
fruits and vegetables has been associated with protection
against bladder cancer in many s t u d i e ~ . ~
Alsingle
. ~ ~ study
examined the role of tomatoes, lycopene,and bladder can-
cer risk.149Serum micronutrient profiles were quantitated,
43
and only lycopene and selenium concentrations were
found to be inversely related to risk. The effects of lyco-
pene on the development of superficial urinary bladder
carcinoma induced by nitrosamines were evaluated in
rats.'50Lycopene was provided at 0.0025% in drinking wa-
ter. Lycopene caused a slight and nonsignificant reduc-
tion in the number of transitional cell carcinomas. In the
same study, a nonsteroidal anti-inflammatory agent
(piroxicam) was also evaluated and found to be a more
effective agent than lycopene or p-carotene for the pre-
vention of bladder carcinoma.
Lycopene and Prostate Cancer
Prostate cancer is now one of the most common malignan-
cies among men in affluent natiomg2Two prospective
studies have evaluated the relationship between tomato
consumption and the risk of prostate cancer.151Js2One
study"O was conducted in a cohort of Seventh Day
Adventist men who completed a dietary questionnaire in
1976with subsequentmonitoring for cancer incidence over
a 6-year follow-up. Consumption of tomato products or
beans, lentils, and peas was significantly associated with
a lower risk of prostate cancer. The relative risk was 0.60
for men who consumed tomatoes more than five times a
week, compared with those consuming less than one serv-
ing per week. The largest and most comprehensive study
of tomato consumption in prostate cancer risk was de-
rived from the Health Professionals Follow-Up study, a
large cohort of men who completeda 131-item FFQ in 1986
and every few years thereafter. Between 1986 and 1992
more than 800 new cases of prostate cancer were diag-
nosed within the cohort. The estimated intakes of total
carotenoids, p-carotene, a-carotene, lutein, and p-cryp-
toxanthin were not associated with a risk of prostate can-
cer. In contrast, higher estimated lycopene intake was in-
versely related to risk of prostate cancer.The specific food
items that contribute to dietary lycopene intake were care-
fully assessed. Of the fruits and vegetables examined, to-
mato sauce, tomatoes, and pizza accounted for 82% of the
total intake. A risk reduction of 35% was observed based
on a consumption frequency of greater than 10 servings
of tomato products per week versus less than 1.5 servings
per week. The protective effect was even stronger when
the analysis focused upon the risk of more advanced or
aggressive prostate cancer (relative risk 0.47). Tomato
sauce exhibited the strongest inverse associationwith risk
for any one specific food item, with a relative risk of 0.66
(CI 0.49-0.90).
Two relatively small nested case-control studies ex-
amined serum carotenoid profiles in prospectively col-
lected samples and the relationship with subsequent pros-
tate cancer incidence. The Washington County study used
serum obtained in 1974 from 25,802 participant^.'^^ The
serum lycopene levels from men who developed prostate
44
cancer over the following 13 years were compared with
those of a matched group of 103 control subjects of the
same age and race. A 6.2% lower mean concentration of
lycopene was observed in men developing prostate can-
cer compared with controls, with a relative risk of 0.50 (CI
0.20-1.29) for the high versus the low quartile of serum
lycopene. The relative risk was even stronger (relative
risk = 0.35) in men less than 70 years of age. This study
was very small, however, and heterogeneity in serum con-
centrations is typically very large, thus limiting the power
of the study. Also, these associations did not reach sta-
tistically significant levels.
A serum carotenoid study was conducted in a cohort
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of 6860 Japanese-Americanmen living in Hawaii between
1971 and 1993who provided a single blood specimen col-
lected during 1971-1 975.154 Histologically confirmed pros-
tate cancer was observed in 142 cohort members by 1993.
The serum concentrations of carotenoids in the samples
collected years earlier were compared between cases and
matched controls. No association between serum lyco-
pene and risk of prostate cancer 20 years later was ob-
served. However, we should be cautious about interpret-
ing this null association because of the limited power, the
long time period between blood sampling and analysis,
the large number of prostate cancers identified
serendipitously by transurethral resection of prostate
(TURP) for benign prostatic hypertrophy, and the overall
low concentration of lycopene in the serum of men in Ha-
waii.
If lycopene indeed contributes to lower risk of pros-
tate cancer, the mechanisms remain speculative. Lycopene
may act within the host to alter relevant processes, such
as hormone status, in a fashion that inhibits the progres-
sion of prostate cancer. We speculate that an effect on the
prostate may be more direct. We completed a study to
determine the concentrations of carotenoids and lycopene
isomers within human prostate tissue59and observed a
diverse array of carotenoids in human prostate tissue.
Lycopene exhibited the highest median concentration com-
pared to other cartenoids. The range of lycopene observed
in human prostate tissue extended from the undetectable
range to 1.8 nM/g, and total carotenoids within the pros-
tate ranged from 0.75 to 5 nM/g.
The proportion of lycopene distributed among all-
trans versus cis isomers varies significantly between food
products, human serum, and prostate tissue. All-trans
lycopene is predominant in tomatoes and tomato-based
foods and accounts for approximately 90% of total lyco-
pene, with the remainder distributed among several small
cis isomer peaks. In contrast, all-trans lycopene accounts
for only 10-25% and cis isomers for 75-90% of total lyco-
pene in prostate tissue. The cis isomers were distributed
among 14-18 peaks in human prostate tissue and 12-13
peaks in serum. Serum all-trans lycopene averaged about
Nutrition Reviews, Vol. 56, No. 2
40%, whereas cis isomers accounted for approximately
60%. The biologic factors that account for the increased
proportion of cis isomers in serum and prostate tissue
compared with the diet remain to be defined. Overall, the
hypothesis that the consumption of tomato products re-
duces prostate cancer risk via lycopene warrants further
research, but much more evidence is necessary before a
causal relationship can be established.
CardiovascularDisease
Cardiovasculardisease remains the leading cause of mor-
bidity and mortality in most industrialized nations and is
rapidly becoming a major disease entity in many develop-
ing countries. Strategies that can significantly reduce the
progression of atherosclerosis include reduced smoking,
early detection and control of hypertension and diabetes,
and treatment of hyperlipidemias. Many dietary factors
may also be important, and much emphasis has been
placed on carotenoids and antioxidant nutrients such as
vitamins E and C. Accumulating evidence favors the hy-
pothesis that oxidatively modified macromolecules, par-
ticularly those derived from lipoproteins deposited in the
vessel wall, may be critical factors that initially activate
the cellular and cytokine networks involved in lesion for-
mation and progre~sion.'~~J~ The possibility that caro-
tenoids, including lycopene, may be related to the patho-
genesis of cardiovascular disease is a viable hypothesis
but remains to be thoroughly evaluated.
It has been proposed that carotenoids in conjunction
with vitamins E and C may protect lipoproteins and vas-
cular cells from oxidative damage.'57In general, many of
the observational epidemiologic studies support the hy-
pothesis that foods rich in carotenoids and antioxidant
vitamins are associated with reduced risk of atheroscle-
rotic vascular disease.95However, several large-scale in-
tervention trials with p-carotene or vitamin E have pro-
vided inconclusive r e ~ u l t s .Thus
~ ~ far,
~ ~little
~ ~of' ~the vas-
cular biology or atherosclerosis literature has focused on
lycopene. Carotenoids have been detected in lipid-rich
atherosclerotic plaques, although concentrations are very
low (lycopene at 0.049 f 0.065 nM per M of free choles-
ter01).I~~A recent multicenter study was conducted in men
with myocardial infarction and matched controls in 10 Eu-
ropean countries.159 Adipose tissue needle aspiration bi-
opsies were obtained from each participant and analyzed
for carotenoid profiles and tocopherols. After adjusting
for age, body mass, socioeconomic status, smoking, hy-
pertension, and family history, the lycopene concentra-
tion remained independently protective, with an OR of
0.52 for the 10th versus the 90th percentiles. Interestingly,
the protective effect was attenuated in smokers and in
those with lower concentrations of adipose tissue poly-
unsaturated fatty acids. However, these findings are not
supported by an earlier case-control study examining se-
Nutrition Reviews, Vol. 56, No. 2
rum carotenoids, rather than adipose tissue concentra-
tions, and risk of myocardial infarction.I6O
The ability of lycopene to modulate cholesterol rne-
tabolism was recently investigated in cell culture and a
very small clinical trial. The incubation of human mac-
rophage cell lines with lycopene resulted in inhibition of
cholesterol synthesis and augmentation of macrophage
LDL receptors. Dietary supplementation of 60 mg lyco-
penelday in six males for 3 months was associated with a
14% reduction in plasma LDL cholesterol concentrations.
The authors propose that lycopene may be a modest
hypocholesterolemic agent secondary to the inhibition of
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macrophage 3-hydroxy-3-methyl-glutaryl-coenzyme-A
(HMGCoAreductase), the rate-limitingenzyme in choles-
terol biosynthesis. Interestingly, pharmaceutical agents
used in the treatment of hyperlipidemias and cardiovas-
cular disease can reduce semm concentrations of lyco-
pene. Studies with cholestiramine showed lower serum
concentrations of lycopene by approximately 30% com-
pared with baseline,whereas probucol reduced serum caro-
tenoids, including lycopene, by 30-40%.4J62Probucol,
which has both lipid-lowering and antioxidant properties,
may reduce circulating lycopene via reductions in lipo-
protein particle size and by competition between the drug
and carotenoids for incorporation into very-low-density
lipoproteins(VLDL).162
Clearly, much more work needs to be done to unravel
the complexities of lycopene and cardiovascular disease.
In addition to its potential role in protecting against oxida-
tive damage within serum lipoproteins and the evolving
lipid-rich plaque, much more effort should be devoted to
how lycopene and other carotenoids may influence the
functions of platelets, endothelial cells, vascular smooth
muscle cells, and the immune cells that infiltrate develop-
ing plaques and participate in acute vascular events.
Acquired Immune Deficiency Syndrome (AIDS)
Several studies have documented reduced concentrations
of micronutrients in patients with human immunodefi-
ciency virus (HIV) infection, despite dietary intakes that
are predicted to be adequate. One study reported that
HIV-positive women had lower serum concentrations of
lycopene, a-carotene, and p-carotene, particularly in those
with more severe infections who exhibited lower CD4+
helper cell ~ 0 u n t s . IReduced
~~ serum concentrations of
lycopene were observed in children infected with HIV, and
the severity of depletion was correlated with the reduc-
tion in CD4+ helper counts.164The relationship between
serum micronutrient status and vertical transmission of
HIV from mother to child has been i n v e ~ t i g a t e dPrevi-
.~~~
ous studies in Africa suggest that HIV-1 transmission from
mothers to babies is associated with maternal vitamin A
status. In the United States, a study of serum carotenoids
showed no relationship between serum concentrations of
45
vitamin E, P-carotene, or lycopene with risk of HIV- 1ver-
tical transmission. Overall, it appears that the reductions
in circulating antioxidant concentrations may reflect a
metabolic phenomenon associated with HIV infection. A
major contribution to these findings may be lipid malab-
sorption, which is common in progressive HIV disease.
Although these observations are intriguing, it is prema-
ture to conclude that lycopene or any carotenoid partici-
pates in the pathogenesis of HIV infection and the devel-
opment of symptoms characteristic of AIDS.
Diseases of the Central Nervous System
It has been proposed that oxidative damage may underlie
the pathogenesis of degenerative and immune-mediated
central nervous system illnesses, such as Alzheimer’s dis-
ease, Parkinson’s disease, and multiple sclerosis. At this
time, very few studies have investigated the potential role
of carotenoids in influencing the progression of these ill-
n e ~ s e s . ~Currently,
.’~~ very few investigators have at-
tempted to evaluate the concentrations of carotenoids
within the central nervous system, in particular the differ-
ent locations within the central nervous system that may
be selectively influenced by degenerative processes. Our
preliminary studies in rodents fed lycopene suggest that
concentrations of lycopene in the central nervous system
are lower than in most other tissues.
Summary
Lycopene has been a major carotenoid in the human diet
for only the last few centuries. Tomatoes account for the
majority of lycopene ingestion. Tools to assess lycopene
intake and quantitate its concentration in blood and tis-
sue are primarily limited to the last decade. Interest in the
role lycopene may play in health and disease has grown
enormously in a few years and is now a common topic for
discussion among scientists, physicians, dietitians, and
the popular news media. It should be recognized, how-
ever, that most of the health benefits attributed to lyco-
pene are derived from studies of estimated dietary intake
or blood concentrations, which reflect the selection of
tomato products for consumptionrather than supplements.
The availability of lycopene-enriched products for pur-
chase by the public from the “health food” industry, be-
fore evidence has been developed to support the benefi-
cial effects of these products, should be a concern of all
nutrition scientists and medical practitioners. Currently,
there is inadequate information on potential risks, dose-
response relationships, appropriate timing of intake rela-
tive to stages of disease processes, pharmacokinetics or
mechanisms of action for purified lycopene preparations,
and which disease processes may be inhibited by pharma-
cologic lycopene supplements. It is imperative that we
undertake and complete fundamental studies concerning
46
the biology of lycopene, including absorption, metabo-
lism, excretion, and biologic functions in experimental
models and humans. Until additional data have been gen-
erated, our recommendations for the public should em-
phasize the consumption of a diet abundant in a diverse
array of fruits and vegetables, including tomatoes and
other sources of lycopene.
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