The Functions of Tomato Lycopene and Its Role in Human Health

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The Functions of Tomato Lycopene and Its Role in Human Health

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Jan 17, 2005 21:50 PST

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http://www.herbalgram.org/herbalgram/articleview.asp?a=2696

 

HerbalGram. 2004;62:49-56 © American Botanical Council

by Joseph Levy, PhD and Yoav Sharoni, PhD

 

Introduction

 

Carotenoids, compounds found in fruits and vegetables, benefit human

health by playing an important role in cell function. The dietary

necessity of the carotenoid beta-carotene, the precursor of vitamin A,

has been recognized for many decades. More recently, lycopene has

attracted substantial interest among carotenoid and medical researchers.

 

 

Lycopene is the red carotenoid found predominantly in tomatoes and in a

few other fruits and vegetables. Claims have been made that lycopene may

be beneficial in diseases such as cancer and coronary heart disease as

well as other chronic conditions. These claims have been studied

extensively, through epidemiological studies, biochemical investigations

of lycopene’s properties, and thorough examination of lycopene’s

bioavailability from tomato-based diets. This article summarizes the

current state of knowledge of the properties of lycopene, its possible

role in human health, and areas for future lycopene research.

 

 

Lycopene’s function in the human body

 

Although not considered an essential nutrient, research has shown that

lycopene may have various benefits for human health. As a major

carotenoid in human blood, lycopene protects against oxidative damage to

lipids, proteins, and DNA.

 

Lycopene is a potent quencher of singlet oxygen (a reactive form of

oxygen), which suggests that it may have comparatively stronger

antioxidant properties than other major plasma carotenoids.

 

Lycopene has been found to be a potent and specific inhibitor of cancer

cell proliferation, which is regulated by an elaborated cellular process

called “cell cycle.” Rapid and uncontrolled cell division is a hallmark

of cancer cell metabolism; lycopene’s activity in retarding cell cycle

progression may explain its demonstrated activity in retarding the

spread of certain types of cancer.

 

Lycopene may prevent malignant transformation (the cellular process

which describes the transformation of a normal cell into a cancer cell).

 

 

Contact inhibition is one of the mechanisms that controls excessive cell

division. By this mechanism, a cell, in crowded surroundings, will stop

multiplying. Special structures in the cell membrane, termed a

“gap-junction,” function as communication channels between cells.

 

Normal cells are both contact-inhibited and have a functional

gap-junction whereas most tumor cells exhibit fewer of these structures.

Lycopene was found to induce the formation of the protein connexin 43,

one of the major building blocks of these channels, and thereby to

restore gap junctions.

 

Lycopene induces Phase II enzymes which help to eliminate carcinogens

and toxins from the body. The change of the levels of so many regulatory

proteins is related to lycopene’s ability to modulate various

transcription factors which are key players in the process of new

cellular protein synthesis.5, 6

 

 

Structure, intake absorption, and transport

 

Lycopene is defined chemically as an acyclic carotene with 11 conjugated

double bonds, normally in the all-trans configuration (Fig. 1). The

double bonds are subject to isomerization, and various cis isomers

(mainly 5, 9, 13, or 15) are found in plants and also in blood plasma.

 

Since the human body is unable to synthesize carotenoids from

endogenously produced biochemicals, the body is totally dependent on

dietary sourced (exogenous) carotenoids.

 

In general, tomato fruit and tomato-based food products provide at least

85% of dietary lycopene in humans.

 

The remaining 15% are usually obtained from watermelon, pink grapefruit,

guava, and papaya—all fruits that are dietary sources of lycopene,

although at much lower levels than tomatoes (Table 1).

 

 

 

Table 1: Lycopene content of common foods Food Type

Amount mg per 100 gr. References

 

Guava Fresh, pink 5.4 7

Organic Tomatoes Fresh, red 3.1-7.7 8

Organic Tomato Juice 7.83 8

Organic Tomato Paste 30.07 8 8

Grapefruit Fresh, pink 3.36 8

Watermelon Fresh, red 4.1 7

Organic Ketchup 16.6 7

Organic Pizza sauce 32.9 8

Organic Spaghetti sauce 17.5 9

Papaya Fresh, red 2.0-5.3 10

 

 

Tomato juice, tomato soup, ketchup, pizza, and spaghetti sauce are the

major contributing tomato products in the diet. Uptake of carotenoids

from the diet has been studied for many years.

 

The bioavailability of dietary lycopene appears to be dependent upon

several factors. It is absorbed better from lipid-rich diets and from

cooked, rather than raw foods.

 

Once ingested, lycopene appears in plasma, initially in the chylomicrons

(microscopic emulsified fat particles found in the blood serum and lymph

that result from fat digestion) and VLDL (very low-density lipoprotein)

fractions and later in LDL (low-density lipoproteins, the so-called

“bad” cholesterol) and HDL (high-density lipoproteins, often called

“good” cholesterol). The highest levels are found in LDL. Serum

concentrations vary markedly from about 20 to 500 mcg/liter of serum

with large interpersonal variations.

 

Several lines of evidence suggest that oxidatively modified LDL is

damaging to the arterial wall, and that atherosclerosis can be

attenuated by natural antioxidants.

 

As reported by Fuhrman et al., tomato lycopene, alone or in combination

with other natural antioxidants, inhibits LDL oxidation.12 Moreover, the

same group reported that dietary supplementation of organic tomato’s

lycopene (60 mg/day) when administered to 6 males for a 3-month period

resulted in a significant reduction in their plasma LDL cholesterol.

This was in agreement with their in vitro results showing that lycopene

suppresses cholesterol synthesis and augments LDL receptor activity in

macrophages.

 

Lycopene is found in most human tissues but is not accumulated

uniformly. There is preferential accumulation of lycopene, particularly

in the " adrenals " and testes.

 

The confirmed ability to increase lycopene levels in tissues is one

prerequisite for using it as a dietary supplement to improve health.

Indeed, it has recently been reported that supplementation of tomato

lycopene oleoresin in volunteers undergoing elective surgery produced a

significant increase in carotenoids in plasma, skin, and adipose

tissues.

 

Little is known about the metabolism or degradation of lycopene in

mammals. A number of oxygenated metabolites have been found in plasma

and tissues, but more studies are needed in order to estimate their

physiological roles, if any.

 

Clinical research demonstrates that lycopene is absorbed more readily

from heat processed tomato products than from uncooked sources and

absorption is improved by the presence of nutrient- dense unrefined

extra virgin oils.

 

 

Lycopene benefits from synergistic relationship with other

micronutrients

 

When reviewing data related to the chemoprevention of various diseases,

it becomes evident that the use of a single carotenoid, or any other

micronutrient which has been successful in in vitro and animal models,

does not prove as favorable in human intervention studies. That is,

there is no magic bullet.

 

In fact, accumulating evidence suggests that a concerted, synergistic

action of various micronutrients is more likely to be the basis of the

disease-prevention activity of a diet rich in organic vegetables and

fruit.

 

Indeed, the sources of lycopene used in most of the human studies

reviewed here were either prepared tomato products or tomato extracts

containing lycopene and other tomato micronutrients and carotenoids in

various proportions.

 

Pure lycopene has not been tested as a single agent in human prevention

studies. On the other hand, many studies showing the beneficial effect

of lycopene in alleviating chronic conditions have been conducted in

which the subjects were provided with tomato-based foods, or tomato

extracts, but not with the pure compound.

 

For example, the oleoresin preparation used in many of these studies

also contained other tomato carotenoids such as phytoene, phytofluene,

and beta-carotene (Fig 1).

 

A critical view of these studies might question whether compounds other

than lycopene in tomato may be responsible for the benefit; however, in

vitro studies support synergistic action of the tomato carotenoids and

other antioxidants present in tomato.

 

This approach was tested in a recent study20 that compared the potency

of freeze-dried whole tomatoes (tomato powder) or pure lycopene in a rat

model of prostate cancer. Rats were treated with the carcinogen NMU

(N-methyl-N-nitrosourea) combined with androgens to stimulate prostate

carcinogenesis, and the ability of these two preparations containing

lycopene to enhance survival was compared.

 

Mortality with prostate cancer was lower by 25% (P = 0.09) for rats fed

the tomato powder diet than for rats fed control feed. Prostate cancer

mortality of rats fed pure lycopene was similar to that of the control

group.

 

The authors concluded that consumption of tomato powder but not pure

lycopene inhibited prostate carcinogenesis, suggesting that tomato

products contain other compounds, besides lycopene, that modify prostate

carcinogenesis.

 

In an accompanying editorial, Gann et al.21 note that this study

contributes to the debate about whether cancer prevention is best

achieved with whole foods or with single compounds.

 

They point out that carotenoids and other secondary plant compounds have

evolved as sets of interacting compounds, a complexity that limits the

usefulness of reductionist approaches seeking to identify single

protective compounds. Unfortunately, the ensuing coverage of the results

of this study in the media included headlines declaring that lycopene

was found to be ineffective in treating prostate cancer, while ignoring

the beneficial results from the tomato powder.

 

 

The protective role of lycopene in preventing degenerative diseases

 

A comprehensive review of the epidemiological literature on the relation

of tomato consumption and cancer was published by Giovannucci.22 He

found that among 72 studies, 57 reported inverse associations between

tomato intake or blood lycopene level and the risk of cancer at a

defined anatomic site. Thirty-five out of 57 of these inverse

associations were statistically significant.

 

None of the cited studies indicated that higher tomato consumption or

blood lycopene level significantly increased the risk of cancer at any

of the investigated sites. The evidence for a benefit was strongest for

cancers of the prostate, lung, and stomach. Data were also suggestive of

a benefit for cancers of the pancreas, colon and rectum, esophagus, oral

cavity, breast, and cervix.

 

Giovannucci suggests that lycopene may contribute to these beneficial

effects of tomato containing foods, but this has not been conclusively

proven. In addition, as discussed above, the anticancer properties can

also be explained by interactions among multiple components found in

tomatoes. Cancer of the prostate continues to be the focus of lycopene

research and, following Giovannucci’s comprehensive review, several new

studies have appeared in the literature.

 

In a recently published meta-analysis, Etminan et al.23 tested the

assumption that intake of tomato products reduces the risk of prostate

cancer. Researchers reviewed 21 studies involving the daily intake of

one serving or more of tomatoes, tomato products, or lycopene

supplements.

 

The results show that tomato products may play a role in the prevention

of prostate cancer. However, this effect is modest (11% reduction in

cancer risk) and restricted to high amounts of tomato intake.

 

Moreover, the preventive effect was slightly stronger for high intakes

of cooked tomato products than for high intakes of raw tomatoes,

probably due to the bioavailability of lycopene, which is increased with

processing, heat, and presence of fat.

 

It was previously reported that there is low correlation between dietary

lycopene intake and serum level, probably due to the saturation of

absorption at higher lycopene intake levels. Thus, stronger protective

effect was observed in studies that directly measured plasma lycopene as

compared to those that estimated lycopene intake. The authors concluded

that further research is needed to determine the type and quantity of

tomato products and their role in preventing prostate cancer.

 

An ecologic (multi-country statistical) approach has also found that

tomatoes reduce the risk of prostate cancer, most likely due to the

action of lycopene.26 High lycopene intake was associated with lower

risk for gastric cancer.

 

In an integrated series of studies in Italy, tomato consumption showed a

consistent inverse relationship to the risk of digestive tract neoplasm

(abnormal new tissue growth, tumor). Two small-scale, preliminary

intervention studies on prostate cancer patients were carried out with

natural tomato preparations. In one, Chen et al.29 showed that after

dietary intervention, serum and prostate lycopene concentrations were

increased and oxidative DNA damage both in leukocytes and in prostate

tissue was significantly lower. Furthermore, serum levels of

prostate-specific antigen (PSA) decreased after the intervention.

 

In the other study, Kucuk et al.30 reported that supplementation with

tomato extract in men with prostate cancer modulates the grade and

volume of prostate intraepithelial neoplasia and tumor, the level of

serum PSA, and the level of biomarkers of cell growth and

differentiation. High lycopene intake was associated with lower risk for

breast cancer in women.31, 32

 

 

Coronary heart disease

 

Coronary heart disease (CHD) is one of the primary causes of death in

the Western world. The emphasis of research so far has been on the

relationship between serum cholesterol levels and the risk of CHD. More

recently, oxidative stress induced by reactive oxygen species (ROS) is

also considered to play an important part in the etiology of this

disease.

 

Dietary lycopene has been shown in in vitro studies to prevent the

formation of oxidized LDL, a key player in the pathogenesis of

atherosclerosis and CHD.

 

The source of lycopene used in most of these studies was either tomato

food products or tomato-derived lycopene extracts. Both of these sources

contain various proportions of other carotenoids in addition to

lycopene; therefore, it is not possible to attribute the demonstrated

effects solely to lycopene.

 

The evidence in support of the role of lycopene in the prevention of CHD

stems primarily from the epidemiological observations of normal and

at-risk populations. The most impressive population-based evidence comes

from a multi-center case-control study (the EURAMIC study) in which

subjects from 10 European countries were evaluated for a relationship

between their antioxidant status and acute myocardial infarctions.

 

After adjusting for a range of dietary variables, only lycopene levels,

not beta-carotene levels, were found to be protective.33 These results

were also confirmed by another study (the Rotterdam Study).34

 

Serum lycopene concentration may play a role in the early stages of

atherosclerosis. Increased thickness of intima-media (the innermost

lining of a blood vessel, including the middle, muscular layer in the

wall of the blood vessel) has been shown to predict coronary events.

 

A low serum lycopene concentration, prevalent in eastern Finland, was

associated with an increased thickness of the intima-media.35, 36 In

Lithuanian and Swedish populations showing diverging mortality rates

from CHD, lower blood lycopene levels were found to be associated with

increased risk and mortality from CHD.

 

Recently a prospective, nested, case-control study was conducted by

Harvard University researchers on 39,876 women. The study showed that

higher plasma lycopene concentrations are associated with a lower risk

of cardiovascular disease in middle-aged and elderly women.

 

Moreover, as noted previously by the same group,39 the possible inverse

associations with cardiovascular disease for higher levels of

tomato-based products (particularly tomato sauce), suggest that dietary

lycopene or other phytochemicals consumed as oil-based or oil-containing

tomato products confer cardiovascular benefits.

 

 

Skin protection

 

Oral sun protectants are probably more efficient than topical ones, as

most sun exposure is incidental to daily living and not related to

vacation time when topical sunscreens are commonly used.40 (This

hypothesis has not been adequately investigated or confirmed.) Studies

are scarce, however, on the protective effect of oral carotenoid

supplements against skin responses to sun exposure.

 

The protective effects are thought to be related to the antioxidant

properties of the carotenoids. During ultraviolet (UV) irradiation, skin

is exposed to photo-oxidative damage induced by the formation of ROS.

Photo-oxidative damage affects cellular lipids, proteins, and DNA and is

considered to be involved in the formation of erythema, premature aging

of the skin, photodermatoses, and skin cancer.

 

Carotenoids, and especially lycopene, are efficient scavengers of ROS.40

Several animal studies and in vitro experiments provided evidence that

carotenoids and tocopherols prevent UV light–induced skin lesions and

protect against skin cancer.

 

Plasma and skin carotenoid concentrations decrease with UV irradiation;

however, it is interesting that lycopene is lost preferentially over

other carotenoids.

 

Exposure of a small area of the forearm skin to UV light resulted in a

reduction in skin lycopene. The same UV dose, however, did not result in

significant changes in skin beta-carotene concentration. The authors

concluded that when skin is subjected to UV light stress, more skin

lycopene is destroyed as compared with beta-carotene, suggesting that

lycopene plays a role in mitigating oxidative damage in tissues.

However, other interpretations of these results are possible.

 

In a recent study,40 the efficacy of a mixture of carotenoids containing

beta-carotene, lutein, and lycopene was compared to beta-carotene alone

for protection from UV induced skin erythema. Caucasian volunteers were

tested in a placebo-controlled, parallel study. The intake of either

beta-carotene or a mixture of carotenoids similarly increased total

carotenoids in skin from week 0 to week 12. No changes in total

carotenoids in skin occurred in the control group. The intensity of

erythema 24 hours after irradiation was diminished in both groups that

received carotenoids and was significantly lower than baseline after 12

weeks of supplementation.

 

Long-term supplementation for 12 weeks with 24 mg/day of a carotenoid

mix supplying similar amounts of beta-carotene, lutein, and lycopene

ameliorates UV-induced erythema in humans. The superior protection with

mixtures may be due to different absorption wavelengths of the various

compounds, leading to a greater absorption potential of the broader

range of wavelengths. In another study, the same research group

demonstrated that supplementation with tomato, a natural source for

lycopene and other carotenoids (see Fig. 1), protects against UV-induced

skin erythema in humans.42

 

 

Mechanism of action

 

a. Antioxidant Activity

 

Oxidative stress is recognized as one of the major contributors to the

increased risk of cardiovascular disease and cancer. Among the common

carotenoids lycopene stands as the most potent antioxidant as

demonstrated by in vitro experimental systems.

 

Based on this study the antioxidant potency of carotenoids can be ranked

as follows: lycopene > [is greater than] alpha-tocopherol >

alpha-carotene > beta-cryptoxanthin > zeaxanthin > beta-carotene >

lutein. Mixtures of carotenoids were more effective than the single

compounds.19 This synergistic effect was most pronounced when lycopene

or lutein was present. The superior protection of mixtures may be

related to the specific positioning of different carotenoids in cell

membranes.

 

Several studies of tomato consumption demonstrate the antioxidant

properties in humans. For example, recently it was found that daily

consumption of a tomato product containing 15 mg lycopene plus other

tomato phytonutrients significantly enhanced the protection of

lipoproteins from ex vivo oxidative stress.43 These results indicate

that lycopene absorbed from tomato products may act as an in vivo

antioxidant.

 

b. Inhibition of cancer cell proliferation (cell cycle)

 

Lycopene has been found to inhibit proliferation of several types of

cancer cells, including those of breast, prostate, lung, and

endometrium. The inhibitory effects of lycopene on mammary and prostate

cancer cell growth were not accompanied by apoptotic (programmed) or

necrotic (resulting from injury or disease) cell death, a mechanism

related to the action of some drugs but not to micronutrients frequently

consumed in the human diet.

 

This effect was accompanied by inhibition of cell cycle progression from

the G0/G1 to the S phase as measured by flow cytometry.3 The inhibition

of cell proliferation correlated with a decrease in cyclin D1 protein

levels which is a key regulator of this process.

 

It is well documented that growth factors affect the cell cycle

apparatus (primarily during G1 phase) and that the main components

acting as growth factor sensors are the D-type cyclins.44 Moreover,

cyclin D1 is known to act as an oncogene (a gene whose dysregulation

causes normal cells to become cancerous) and is found to be

over-expressed in many breast cancer cell lines as well as in primary

tumors.45 Thus, the decrease in cellular cyclin D1 level by lycopene

provides a mechanistic explanation for the anticancer activity of the

carotenoid.

 

c. Interference with growth factors stimulation of cancer cell

proliferation

 

The growth stimulation of mammary cancer cells by insulin-like growth

factor 1 (IGF-1) was markedly reduced by physiological concentrations of

lycopene in experimental in vitro studies.2, 46 The significance of this

finding for cancer prevention is related to independent epidemiological

findings that elevated IGF-1 levels increase lifetime risks of breast

and prostate cancer.47, 48 If lycopene interference with IGF-1

stimulation of tumor cell growth is confirmed in clinical studies, this

would provide a strong rationale for recommending increased intake of

lycopene, particularly via tomato-based food products, for cancer

prevention.

 

d. Cancer prevention by inducing phase II enzymes

 

Induction of phase II enzymes, which conjugate reactive electrophiles

(chemicals that are attracted to electrons or tend to accept electrons

from other chemicals) and act as indirect antioxidants, appears to be an

effective means for achieving protection against a variety of

carcinogens in animals and humans. Bhuvaneswari et al.49 associated the

chemopreventive (cancer-preventive) effect of lycopene on the incidence

of DMBA-induced hamster buccal (cheek, mouth) pouch tumors with a

simultaneous rise in the level of reduced glutathione, enzymes of the

glutathione redox cycle, and glutathione S-transferase (GST) in the

buccal pouch mucosa. (Note: DMBA is a 9,10-dimethylbenz-a-anthracene, a

potent tumor-initiating compound.) These results suggest that the

lycopene-induced increase in the levels of GSH and the phase II enzyme

GST inactivates carcinogens by forming conjugates (chemicals formed by

two or more compounds), products that are less toxic and readily

excreted.

 

e. Regulation of transcription

 

Transcription is the process whereby genetic information is carried from

the DNA molecule via the RNA molecule acting as a messenger. This

biochemical route leads to the formation of new proteins by the process

called translation. As discussed above, lycopene modulates the basic

mechanisms of cell proliferation, growth factor signaling, and gap

junctional intercellular communication.50 Additionally, lycopene

produces changes in the expression of many proteins participating in

these processes, e.g., connexins, cyclins, and phase II enzymes.

Therefore, the question that arises is “By what mechanisms does lycopene

affect so many diverse cellular pathways?” The changes in the expression

of multiple proteins suggest that the initial effect of lycopene

involves modulation of transcription; this process is reviewed by

Sharoni et al. in a recent publication.51 This may be due to either

direct interaction of the carotenoid molecules or their derivatives with

transcription factors (e.g., with ligand-activated nuclear receptors52)

or indirect modification of transcriptional activity (e.g., via changes

in status of cellular redox, which affects redox-sensitive transcription

systems53).

 

 

 

Safety of lycopene

 

The safety issue for carotenoids attracted much attention after the

publication of the beta-carotene supplementation trials, which yielded

negative results. It is interesting that in those studies an increased

risk for lung cancer was related to a 12- and 16-fold increase in

beta-carotene plasma levels due to supplementation (the CARET and ATBC

studies, respectively).

 

In these studies beta-carotene plasma levels increased from 0.32 µM

before supplementation up to 3.9 and 5.9 µM, respectively. (Note: One

microMolar [µM] denotes a concentration of 1 x 10-6 gram-molecular

weight of solute per liter of solution.)

 

In a third study, which showed no effect for beta-carotene

supplementation (the Physicians’ Health Study),54 only a 5-fold increase

in the carotenoid serum level was achieved. Interestingly, the only

study with positive results after supplementation with beta-carotene was

achieved in Linxian, a Chinese community with very low carotenoid levels

(0.11 µM) before the intervention.54 Although supplementation caused an

11-fold increase in beta-carotene level, the final concentration of

beta-carotene reached was a relatively low 1.5 mM. All these studies

used synthetic beta-carotene. Thus, keeping plasma levels of carotenoids

in the upper range of physiological level, but not higher, may be a good

safety guide. Interestingly, reviewing many studies which measured serum

levels of beta-carotene and lycopene after supplementation suggests that

beta-carotene serum levels are significantly higher than those found for

lycopene. Serum levels reached for beta-carotene are around 3 mM and may

exceed 5 mM after supplementation; on the other hand lycopene levels

above 1.2 mM are rarely seen even after long-term application.

 

Moreover, the serum level achieved for lycopene was not directly

correlated to the amount of the supplemented carotenoid. For example,

supplementation as high as 75 mg/day did not increase lycopene serum

levels more than 1 mM.55, 56 In conclusion, by some unknown mechanism,

lycopene plasma levels after supplementation remain relatively low,

which may provide a safety valve.

 

Several safety studies on formulated synthetic lycopene preparation were

performed in rats and rabbits. The results of these studies demonstrated

the absence of any significant toxicological effects of the tested

materials in animals.57-59 However, the Scientific Committee on Food of

the European Commission found these synthetic preparations to be

unacceptable for use as food because of their high sensitivity to oxygen

and light, which form degradation products with mutagenic activity.60 A

thorough safety review by an independent panel of toxicologists has

resulted in a GRAS (generally recognized as safe) self-affirmation for

Lyc-O-Mato® (LycoRed, Beer-Sheva, Israel), a branded tomato extract that

has been the subject for several of the studies evaluating the effects

of tomato products in dietary supplement form on a variety of disease

parameters.61

 

 

Concluding remarks

 

The scientific research to date has demonstrated an array of health

benefits clearly associated with tomato products in the diet. A look at

the synergy between carotenoids has demonstrated that neither synthetic

lycopene nor tomato lycopene alone will act as a magic bullet.

 

Effectiveness and safety are married together in the whole organic

tomato.

 

Health benefits are derived from the addition of tomato products to the

diet, particularly cooked tomato products containing unrefined oils, or

from supplements of tomato extract suspended in unrefined oils.

 

The natural tomato oil increases the bioavailability of the tomato

phytonutrients. For maximum benefit, dietary supplement customers who

have opted for a nutritional approach should consider products

containing a standardized tomato extract that supplies many of the

active phytonutients in tomato.

 

 

Joseph Levy, PhD and Yoav Sharoni, PhD are professors at the Department

of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion

University of the Negev and Soroka Medical Center of Kupat Holim,

Beer-Sheva, Israel.

 

 

References:

 

1. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient

biological carotenoid singlet oxygen quencher. Arch Biochem Biophys.

1989;274(2):532-538.

 

2. Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent

inhibitor of human cancer cell proliferation than either a-carotene or

b-carotene. Nutr Cancer. 1995;24:257-267.

 

3. Nahum A, Hirsch K, Danilenko M, et al. Lycopene inhibition of cell

cycle progression in breast and endometrial cancer cells is associated

with reduction in cyclin D levels and retention of p27(Kip1) in the

cyclin E-cdk2 complexes. Oncogene. 2001;20(26):3428-3436.

 

4. Zhang LX, Cooney RV, Bertram JS. Carotenoids up-regulate connexin-43

gene expression independent of their provitamin-A or antioxidant

properties. Cancer Res. 1992;52(20):5707-5712.

 

5. Ben-Dor A, Nahum A, Danilenko M, et al. Effects of acyclo-retinoic

acid and lycopene on activation of the retinoic acid receptor and

proliferation of mammary cancer cells. Arch Biochem Biophys.

2001;391(1):295–302.

 

6. Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M. Retinoid

signaling and activator protein-1 expression in ferrets given

beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer

Inst. 1999;91(1):60-66.

 

7. USDA. 1998. USDA-NCI Carotenoid Database for U.S. Foods. Nutrient

Data Lab., Agric. Res. Service, U.S. Dept. of Agriculture, Beltsville

Human Nutrition Research Center, Riverdale, MD.

 

8. Nguyen ML, Schwartz SJ. Lycopene stability during food processing.

Proc Soc Exp Biol Med. Jun 1998;218(2):101-105.

 

9. Hadley CW, Miller EC, Schwartz SJ, Clinton SK. Tomatoes, lycopene,

and prostate cancer: progress and promise. Exp Biol Med (Maywood). Nov

2002;227(10):869-880.

 

10. Mangels AR, Holden JM, Beecher GR, Forman MR, Lanza E. Carotenoid

content of fruits and vegetables: an evaluation of analytic data. J. Am.

Diet Assoc. 1993;93:284-296.

 

11. Bohm V, Bitsch R. Intestinal absorption of lycopene from different

matrices and interactions to other carotenoids, the lipid status, and

the antioxidant capacity of human plasma. Eur J Nutr. Jun

1999;38(3):118-125.

 

12. Fuhrman B, Ben-Yaish L, Attias J, Hayek T, Aviram M. Tomato lycopene

and beta-carotene inhibit low density lipoprotein oxidation and this

effect depends on lipoprotein vitamin E content. Nutr Metab Cardiovasc

Dis. 1997;7:433-443.

 

13. Fuhrman B, Elis A, Aviram M. Hypocholesterolemic effect of lycopene

and beta-carotene is related to suppression of cholesterol synthesis and

augmentation of LDL receptor activity in macrophages. Biochem Biophys

Res Commun. 1997;233(3):658-662.

 

14. Khachik F, Carvalho L, Bernstein PS, Muir GJ, Zhao DY, Katz NB.

Chemistry, distribution, and metabolism of tomato carotenoids and their

impact on human health. Exp Biol Med (Maywood). Nov

2002;227(10):845-851.

 

15. Walfisch Y, Walfisch S, Agbaria R, Levy J, Sharoni Y. Lycopene in

serum, skin and adipose tissues after tomato-oleoresin supplementation

in patients undergoing haemorrhoidectomy or peri-anal fistulotomy. Br J

Nutr. Oct 2003;90(4):759-766.

 

16. Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is

greater from heat-processed than from unprocessed tomato juice in

humans. J Nutr. 1992;122(11):2161-2166.

 

17. Amir H, Karas M, Giat J, et al. Lycopene and

1,25-dihydroxyvitamin-D3 cooperate in the inhibition of cell cycle

progression and induction of differentiation in HL-60 leukemic cells.

Nutr Cancer. 1999;33:105-112.

 

18. Pastori M, Pfander H, Boscoboinik D, Azzi A. Lycopene in association

with alpha-tocopherol inhibits at physiological concentrations

proliferation of prostate carcinoma cells. Biochem Biophys Res Commun.

1998;250(3):582-585.

 

19. Stahl W, Junghans A, deBoer B, Driomina ES, Briviba K, Sies H.

Carotenoid mixtures protect multilamellar liposomes against oxidative

damage: synergistic effects of lycopene and lutein. FEBS Lett.

1998;427(2):305-308.

 

20. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK.

Prostate carcinogenesis in N-methyl-N-nitrosourea

(NMU)-testosterone-treated rats fed tomato powder, lycopene, or

energy-restricted diets. J Natl Cancer Inst. Nov 5

2003;95(21):1578-1586.

 

21. Gann PH, Khachik F. Tomatoes or lycopene versus prostate cancer: is

evolution anti-reductionist? J Natl Cancer Inst. Nov 5

2003;95(21):1563-1565.

 

22. Giovannucci E. Tomatoes, tomato-based products, lycopene, and

cancer: review of the epidemiologic literature. J Natl Cancer Inst.

1999;91:317-331.

 

23. Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato

products and lycopene in the prevention of prostate cancer: a

meta-analysis of observational studies. Cancer Epidemiol Biomarkers

Prev. Mar 2004;13(3):340-345.

 

24. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett

WC. Intake of carotenoids and retinol in relation to risk of prostate

cancer. J Natl Canc Inst. 1995;87:1767-1776.

 

25. Freeman VL, Meydani M, Yong S, et al. Prostatic levels of

tocopherols, carotenoids, and retinol in relation to plasma levels and

self-reported usual dietary intake. Am J Epidemiol. Jan 15

2000;151(2):109-118.

 

26. Grant WB. An ecologic study of dietary links to prostate cancer.

Altern Med Rev. 1999;4(3):162-169.

 

27. Tsubono Y, Tsugane S, Gey KF. Plasma antioxidant vitamins and

carotenoids in five Japanese populations with varied mortality from

gastric cancer. Nutr Cancer. 1999;34(1):56-61.

 

28. La Vecchia C. Tomatoes, lycopene intake, and digestive tract and

female hormone-related neoplasms. Exp Biol Med (Maywood). Nov

2002;227(10):860-863.

 

29. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA

damage in prostate cancer patients consuming tomato sauce-based entrees

as a whole-food intervention. J Natl Cancer Inst. 2001;93(24):1872-1879.

 

 

30. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical

trial of lycopene supplementation before radical prostatectomy. Cancer

Epidemiol Biomarkers Prev. 2001;10(:861-868.

 

31. Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu

M, Leborgne F. Vegetables, fruits, and related nutrients and risk of

breast cancer: a case-control study in Uruguay. Nutr Cancer.

1999;35(2):111-119.

 

32. Hulten K, Van Kappel AL, Winkvist A, et al. Carotenoids,

alpha-tocopherols, and retinol in plasma and breast cancer risk in

northern Sweden. Cancer Causes Control. Aug 2001;12(6):529-537.

 

33. Kohlmeier L, Kark JD, GomezGracia E, et al. Lycopene and myocardial

infarction risk in the EURAMIC Study. Am J Epidemiol. 1997;146:618-626.

 

34. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A,

Witteman JC. Serum carotenoids and atherosclerosis. The Rotterdam Study.

Atherosclerosis. 2000;148(1):49-56.

 

35. Rissanen TH, Voutilainen S, Nyyssonen K, et al. Low serum lycopene

concentration is associated with an excess incidence of acute coronary

events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Br J Nutr. 2001;85(6):749-754.

 

36. Rissanen TH, Voutilainen S, Nyyssonen K, Salonen R, Kaplan GA,

Salonen JT. Serum lycopene concentrations and carotid atherosclerosis:

the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr.

Jan 2003;77(1):133-138.

 

37. Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and

mortality from coronary heart disease in Lithuanian and Swedish men:

concomitant cross sectional study of men aged 50. BMJ.

1997;314(7081):629-633.

 

38. Sesso HD, Buring JE, Norkus EP, Gaziano JM. Plasma lycopene, other

carotenoids, and retinol and the risk of cardiovascular disease in

women. Am J Clin Nutr. Jan 2004;79(1):47-53.

 

39. Sesso HD, Liu S, Gaziano JM, Buring JE. Dietary lycopene,

tomato-based food products and cardiovascular disease in women. J Nutr.

Jul 2003;133(7):2336-2341.

 

40. Heinrich U, Gartner C, Wiebusch M, et al. Supplementation with

beta-carotene or a similar amount of mixed carotenoids protects humans

from UV-induced erythema. J Nutr. Jan 2003;133(1):98-101.

 

41. Ribaya Mercado JD, Garmyn M, Gilchrest BA, Russell RM. Skin lycopene

is destroyed preferentially over beta-carotene during ultraviolet

irradiation in humans. J Nutr. 1995;125(7):1854-1859.

 

42. Stahl W, Heinrich U, Wiseman S, Eichler O, Sies H, Tronnier H.

Dietary tomato paste protects against ultraviolet light-induced erythema

in humans. J Nutr. May 2001;131(5):1449-1451.

 

43. Hadley CW, Clinton SK, Schwartz SJ. The consumption of processed

tomato products enhances plasma lycopene concentrations in association

with a reduced lipoprotein sensitivity to oxidative damage. J Nutr. Mar

2003;133(3):727-732.

 

44. Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995;20(5):187-190.

 

45. Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and

amplification of cyclin genes in human breast cancer. Oncogene.

1993;8(:2127-2133.

 

46. Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell

cycle progression and insulin-like growth factor I signaling in mammary

cancer cells. Nutr Cancer. 2000;36:101-111.

 

47. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like

growth factor-I and prostate cancer risk: A prospective study. Science.

1998;279:563-566.

 

48. Hankinson SE, Willett WC, Colditz GA, et al. Circulating

concentrations of insulin-like growth factor I and risk of breast

cancer. Lancet. 1998;351:1393-1396.

 

49. Bhuvaneswari V, Velmurugan B, Balasenthil S, Ramachandran CR, Nagini

S. Chemopreventive efficacy of lycopene on

7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch

carcinogenesis. Fitoterapia. Dec 2001;72(:865-874.

 

50. Aust O, Ale-Agha N, Zhang L, Wollersen H, Sies H, Stahl W. Lycopene

Oxidation Product Enhances Gap Junctional Communication. Food Chem

Toxicol. 2003;41(10):1399-1407.

 

51. Sharoni Y, Danilenko M, Dubi N, Ben-Dor A, Levy J. Carotenoids and

transcription. Arch. Biochem. Biophys. 2004;In press.

 

52. Stahl W, von Laar J, Martin HD, Emmerich T, Sies H. Stimulation of

gap junctional communication: comparison of acyclo- retinoic acid and

lycopene. Arch Biochem Biophys. 2000;373(1):271-274.

 

53. Levy J, Ben-Dor A, Dubi N, Danilenko M, Zick A, Sharoni Y.

Carotenoids activate the antioxidant response element (are)

transcription system. AACR Annual Meeting. 2004:Abstract 4035.

 

54. IARC Handbook of Cancer prevention. Vol 2 Carotenoids; 1998.

 

55. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein

oxidation: a human dietary intervention study. Lipids .

1998;33(10):981-984.

 

56. Paetau I, Khachik F, Brown ED, et al. Chronic ingestion of

lycopene-rich tomato juice or lycopene supplements significantly

increases plasma concentrations of lycopene and related tomato

carotenoids in humans. Am J Clin Nutr. Dec 1998;68(6):1187-1195.

 

57. Mellert W, Deckardt K, Gembardt C, Schulte S, Van Ravenzwaay B,

Slesinski R. Thirteen-week oral toxicity study of synthetic lycopene

products in rats. Food Chem Toxicol. Nov 2002;40(11):1581-1588.

 

58. Christian MS, Schulte S, Hellwig J. Developmental (embryo-fetal

toxicity/teratogenicity) toxicity studies of synthetic crystalline

lycopene in rats and rabbits. Food Chem Toxicol. Jun 2003;41(6):773-783.

 

 

59. Jonker D, Kuper CF, Fraile N, Estrella A, Rodriguez Otero C.

Ninety-day oral toxicity study of lycopene from Blakeslea trispora in

rats. Regul Toxicol Pharmacol. Jun 2003;37(3):396-406.

 

60. European C. Opinion on synthetic lycopene as a colouring matter for

use in foodstuffs. Annex V to the minutes of the 119th plenary meeting

of the European Scientific committee on food. 1999.

 

61. Burdock Group. Opinion of an Expert Panel on the Generally

Recognized as Safe (GRAS) status of Lyc-O-Mato ® oleoresin 6% as a food

ingredient. The Burdock Group, May 31, 2003.

 

 

 

 

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