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PubMed2002

Lycopene, tomatoes, and the prevention of coronary heart disease.

Coronary heart disease (CHD) is one of the primary causes of death in the Western world. The emphasis 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. Oxidation of the circulating low-density lipoprotein (LDL(ox)) is thought to play a key role in the pathogenesis of atherosclerosis and CHD. According to this hypothesis, macrophages inside the arterial wall take up the LDL(ox) and initiate the process of plaque formation. Dietary antioxidants such as vitamin E and beta-carotene have been shown in in vitro studies to prevent the formation of LDL(ox) and their uptake by microphages. In a recent study, healthy human subjects ingesting lycopene, a carotenoid antioxidant, in the form of tomato juice, tomato sauce, and oleoresin soft gel capsules for 1 week had significantly lower levels of LDL(ox) compared with controls. The antioxidant effects of lycopene have also been shown in four other human trials, including one where lycopene consumption reduced the levels of breath pentane. However, in one recent study, dietary supplementation with beta-carotene but not with lycopene was shown to inhibit LDL oxidation. The sources of lycopene used in most of these studies were either tomato products or lycopene extracted from tomatoes containing other carotenoids in various proportions. Therefore, it is not possible to attribute the effects solely to lycopene. Mechanisms other than the antioxidant properties of lycopene have also been shown to reduce the risk of CHD. Lycopene was shown to inhibit the activity of an essential enzyme involved in cholesterol synthesis in an in vitro and a small clinical study suggesting a hypocholesterolemic effect. Other possible mechanisms include enhanced LDL degradation, LDL particle size and composition, plaque rupture, and altered endothelial functions. Recent epidemiological studies have also shown an inverse relationship between tissue and serum levels of lycopene and mortality from CHD, cerebrovascular disease, and myocardial infraction. However, the most impressive population-based evidence comes from a multicenter case-control study where subjects from 10 European countries were evaluated for relationship between antioxidant status and acute myocardial infarctions. After adjusting for a range of dietary variables, only lycopene levels but not beta-carotene were found to be protective. At present, the role of lycopene in the prevention of CHD is strongly suggestive. Although the antioxidant property of lycopene may be one of the principal mechanism for its effect, other mechanisms may also be responsible. Controlled clinical and dietary intervention studies using well-defined subject populations and disease end points must be undertaken in the future to provide definitive evidence for the role of lycopene in the prevention of CHD. Mechanistic studies must also be initiated to understand the mode of lycopene action.

Antioxidants↗

PubMed1999

Intestinal absorption of lycopene from different matrices and interactions to other carotenoids, the lipid status, and the antioxidant capacity of human plasma.

BACKGROUND: The bioavailability of carotenoids has been investigated in animal studies as well as in human studies, so far mostly for beta-carotene. Only few results exist for lycopene. In recent studies, lycopene was significantly better available from processed tomatoes compared to raw tomatoes, when using daily intakes between 16.5 mg and 75 mg lycopene. AIM OF THE STUDY: In a comparative study the availability of a low oral lycopene dosage of 5 mg/d from different food matrices versus soft gel capsules containing tomato oleoresin was assessed. In addition to the plasma carotenoid content, the effect of lycopene ingestion on other plasma carotenoids, the lipid status parameters, and the antioxidant activity was estimated. METHODS: Twenty-two female adults (20-27 y) were randomized in three groups and were advised to minimize their carotenoid intake for two weeks. After this initial period, two groups received a portion of tomatoes or tomato juice adjusted to a lycopene dose of 5 mg/d, the third group ingested the same dose comprised in soft gel capsules containing tomato oleoresin. During the test period of 6 weeks, the participants continued reducing the intake of carotenoids from food. Fasting blood samples were withdrawn prior to the study, before supplementation started, and then weekly while supplemented. Seven-day dietary records were prepared before the study started and after one week of supplementation. Carotenoids were analyzed by reversed phase HPLC with diode array detection. Dietary records were evaluated using the computer software EBIS 2.1. The plasma total cholesterol, HDL cholesterol, and triglycerides were determined enzymatically. In addition, the antioxidant activity of plasma was estimated by using the TEAC and the TRAP assays. RESULTS: The basal levels of lycopene in plasma were comparable for all groups (0.2-0.3 mumol/l) and decreased significantly during the two weeks of depletion to approximately 50% of the basal values. Other plasma carotenoids such as beta-carotene and beta-cryptoxanthin decreased significantly, too, whereas lutein and zeaxanthin remained unchanged. After supplementation with tomato oleoresin capsules or tomato juice, the plasma lycopene increased significantly, while it remained unchanged during intake of tomatoes. Normal dietary habits were practised of all volunteers before and during the study except vitamin C whose intake was significantly lower during the study period, because the probands were recommended to reduce the intake of fruits and vegetables. Lycopene supplementation did not affect the lipid status parameters of the three groups. After ingestion of lycopene the antioxidant activity of the plasma was not altered. Mean TEAC values were estimated to 0.33 +/- 0.05 mmol/l and TRAP values to 1.0 +/- 0.1 mmol/l and showed no significant differences in all groups during the whole study period. CONCLUSIONS: The bioavailability of lycopene varied significantly depending on the administered matrix. Lycopene from tomato oleoresin capsules and tomato juice (processed tomatoes) was better absorbed from the intestine than lycopene from raw tomatoes. The daily intake of 5 mg lycopene, an intake comparable to the usual daily carotenoid intake, did not affect cholesterol and triglycerides in plasma or its antioxidant capacity.

Adult↗

PubMed2000

Lycopene synergistically inhibits LDL oxidation in combination with vitamin E, glabridin, rosmarinic acid, carnosic acid, or garlic.

Several lines of evidence suggest that oxidatively modified low-density lipoprotein (LDL) is atherogenic, and that atherosclerosis can be attenuated by natural antioxidants, which inhibit LDL oxidation. This study was conducted to determine the effect of tomato lycopene alone, or in combination with other natural antioxidants, on LDL oxidation. LDL (100 microg of protein/ml) was incubated with increasing concentrations of lycopene or of tomato oleoresin (lipid extract of tomatoes containing 6% lycopene, 0.1% beta-carotene, 1% vitamin E, and polyphenols), after which it was oxidized by the addition of 5 micromol/liter of CuSO4. Tomato oleoresin exhibited superior capacity to inhibit LDL oxidation in comparison to pure lycopene, by up to five-fold [97% vs. 22% inhibition of thiobarbituric acid reactive substances (TBARS) formation, and 93% vs. 27% inhibition of lipid peroxides formation, respectively]. Because tomato oleoresin also contains, in addition to lycopene, vitamin E, flavonoids, and phenolics, a possible cooperative interaction between lycopene and such natural antioxidants was studied. A combination of lycopene (5 micromol/liter) with vitamin E (alpha-tocopherol) in the concentration range of 1-10 micromol/liter resulted in an inhibition of copper ion-induced LDL oxidation that was significantly greater than the expected additive individual inhibitions. The synergistic antioxidative effect of lycopene with vitamin E was not shared by gamma-to-cotrienol. The polyphenols glabridin (derived from licorice), rosmarinic acid or carnosic acid (derived from rosemary), as well as garlic (which contains a mixture of natural antioxidants) inhibited LDL oxidation in a dose-dependent manner. When lycopene (5 micromol/liter) was added to LDL in combination with glabridin, rosmarinic acid, carnosic acid, or garlic, synergistic antioxidative effects were obtained against LDL oxidation induced either by copper ions or by the radical generator AAPH. Similar interactive effects seen with lycopene were also observed with beta-carotene, but, however, to a lesser extent of synergism. Because natural antioxidants exist in nature in combination, the in vivo relevance of lycopene in combination with other natural antioxidants was studied. Four healthy subjects were administered a fatty meal containing 30 mg of lycopene in the form of tomato oleoresin. The lycopene concentration in postprandial plasma was elevated by 70% in comparison to plasma obtained before meal consumption. Postprandial LDL isolated 5 hr after meal consumption exhibited a significant (p < 0.01) reduced susceptibility to oxidation by 21%. We conclude that lycopene acts synergistically, as an effective antioxidant against LDL oxidation, with several natural antioxidants such as vitamin E, the flavonoid glabridin, the phenolics rosmarinic acid and carnosic acid, and garlic. These observations suggest a superior antiatherogenic characteristic to a combination of different natural antioxidants over that of an individual one.

Abietanes↗

PubMed2003

Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets.

Higher intake of lycopene is related to a lower risk of lung cancer in human studies. Lung cancer risk is associated with higher plasma levels of insulin-like growth factor I (IGF-I) and/or lower levels of IGF-binding protein 3 (IGFBP-3). However, little is known regarding whether lycopene can inhibit cigarette smoke-induced lung carcinogenesis through modulation of IGF-I/IGFBP-3, cell proliferation, and apoptosis. We investigated the effects of lycopene supplementation at a low dose (1.1 mg/kg/day, which is equivalent to an intake of 15 mg/day in humans) and a high dose (4.3 mg/kg/day, which is equivalent to 60 mg/day in humans) on plasma IGF-I/IGFBP-3 levels, histopathological changes, proliferating cellular nuclear antigen (PCNA) expression, BAD phosphorylation, and apoptosis (caspase 3 assay) in lungs of ferrets with or without cigarette smoke exposure for 9 weeks. We found that ferrets supplemented with lycopene and exposed to smoke had significantly higher plasma IGFBP-3 levels (P < 0.01) and a lower IGF-I/IGFBP-3 ratio (P < 0.01) than ferrets exposed to smoke alone. Both low- and high-dose lycopene supplementations substantially inhibited smoke-induced squamous metaplasia and PCNA expression in the lungs of ferrets. No squamous metaplasia or PCNA overexpression were found in the lungs of control ferrets or those supplemented with lycopene alone. Furthermore, cigarette smoke exposure greatly increased BAD phosphorylation at both Ser(136) and Ser(112) and significantly decreased cleaved caspase 3 in the lungs of ferrets, as compared with controls. The elevated phosphorylation of BAD and down-regulated apoptosis induced by cigarette smoke in the lungs of ferrets was prevented by both low- and high-dose lycopene supplementations. Lycopene levels were increased in a dose-dependent manner in both plasma and lungs of ferrets supplemented with lycopene alone. However, lycopene levels were markedly lower in both plasma and lungs of ferrets supplemented with lycopene and exposed to smoke. Furthermore, smoke exposure increased cis isomers (26% for 13-cis and 22% for 9-cis) of lycopene in the lungs of ferrets, compared with that of ferrets supplemented with lycopene alone (20% for 13-cis and 14% for 9-cis). In conclusion, lycopene may mediate its protective effects against smoke-induced lung carcinogenesis in ferrets through up-regulating IGFBP-3 and down-regulating phosphorylation of BAD, which promote apoptosis and inhibit cell proliferation.

Animals↗

PubMed2005

[In vitro and in vivo pharmaceutical behaviors of lycopene microcapsules].

AIM: To evaluate in vitro release of lycopene microcapsules. Pharmacokinetic parameters of lycopene microcapsule and lycopene powder as reference were estimated after a single dose of oral administration to dogs. The relationship between in vitro dissolution and in vivo absorption was investigated. METHODS: The content of lycopene in the release medium was determined by UV spectroscopy method. Health hybrid male dogs were used as experiment subjects and lycopene powder used as standard to estimate the pharmacokinetics of lycopene microcapsules. HPLC method was used to assay the concentration of lycopene in dog plasma. Pharmacokinetics parameters were estimated by 3P87 program. The drug release percentage in stimulated intestinal fluid was compared with the absorption at a given time point. RESULTS: The release profiles of lycopene from microcapsule showed that the lycopene gelatin microcapsule exhibited enteric property. The pharmacokinetics parameters estimated after oral administration of lycopene powder and lycopene microcapsule in a single dose of 2.5 mg x kg(-1) body weight to dogs were 7.30 h, 15.06 h for T1/2alpha; 28.10 h, 46.76 h for T1/2beta; 22.32 h, 41.03 h for T(max); 1.67 microg x h x L(-1), 2.08 microg x h x L(-1) for AUC(0-infinity), respectively. The concentration-time curves could be fitted to a two-compartment model for both the lycopene powder and the lycopene microcapsule analyzed by 3P87 program. The relationship between in vitro dissolution and in vivo absorption was found to have good correlation (r = 0. 981 9) was found. CONCLUSION: It could be concluded that lycopene microcapsule was a sustained release dosage form. The result of release in vitro could be used to predict the absorption in vivo.

Administration, Oral↗

PubMed2005

Effects of lycopene and tomato paste extracts on DNA and lipid oxidation in LNCaP human prostate cancer cells.

Animal and epidemiological studies point to a cancer preventive/therapeutic role for tomato products and its antioxidant, lycopene. It is hypothesized that lycopene will behave as an antioxidant at low concentrations and as a prooxidant at high concentrations in LNCaP human prostate cancer cell culture systems. We characterized the antioxidant, and prooxidant effects of a hexane extract of tomato paste (TP) and water solubilized lycopene at different concentrations using a prostate cancer cell line. Placebo (5% triglyceride, Roche Inc.) was used as a control. After 6, 24 hr and 48 hr incubation, LNCaP cells were harvested and used for each measurement. Cellular proliferation was determined using the MTT colorimetric assay. Lycopene and TP hexane extract inhibited cell growth in a dose-dependent (0.1-50 microM lycopene) manner and growth inhibition was 55% and 35% at 1 microM lycopene and TP hexane extract, respectively after 48 hr incubation. The levels of 8-hydroxydeoxyguanosine/deoxyguanosine (an oxidative DNA damage product) was significantly increased starting at 5 microM lycopene from both TP hexane extract and pure lycopene after 24 and 48 hr incubation with no protection at the lower concentrations. Malondialdehyde formation (a lipid peroxidation product measured by HPLC separation of the MDA-TBA adduct) was significantly reduced at low concentrations (0.1-1 microM) of lycopene in all treatments. Clinically relevant concentrations of lycopene and the tomato fraction containing lycopene significantly reduced LNCaP cancer cell survival which can only be partially explained by increased DNA damage at high lycopene concentrations (> 5 microM). Low concentrations of lycopene acted as a lipid antioxidant but did not protect DNA.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2007

Effect of lycopene on insulin-like growth factor-I, IGF binding protein-3 and IGF type-I receptor in prostate cancer cells.

PURPOSE: Prostate cancer is the second most common cancer that leads to death in elderly men. The risk of prostate cancer prevalence is often associated with the elevated level of insulin-like growth factor-I (IGF-I) and decreased level of IGF-binding protein 3 (IGFBP-3). Lycopene, a carotenoid, reduces the proliferation of cancer cells and induces apoptosis. Hence, higher intake of lycopene can be associated with the lower risk of prostate cancer. However, the mechanism of action of lycopene in the prevention of prostate cancer is still unclear. The present study was carried out to study the effects of lycopene on the components of IGF system and apoptosis in androgen-independent prostate cancer cells (PC-3 cells). METHODS: PC-3 cells were treated with various concentrations of lycopene, (20, 40 and 60 microM) for 24, 48, 72 and 96 h. IGF-I, IGFBP-3 and IGF-I receptor (IGF-IR) levels in lycopene-treated cells were evaluated. Annexin V and propidium iodide (PI) binding studies were done to assess apoptosis. RESULTS: PC-3 cells treated with lycopene showed a significant decrease in cell proliferation. Lycopene, at a dose of 40 microM, significantly increased the level of IGFBP-3. Lycopene-induced apoptosis was confirmed by annexin V and PI binding. Lycopene-induced DNA fragmentation was absent after 24 h treatment whereas the same was observed after 48 h treatment. There was a significant decrease in the IGF-IR expression after the cells were treated with lycopene and IGF-I. CONCLUSION: The data obtained suggest that the components of the IGF system may act as a positive regulator of lycopene-induced apoptosis in PC-3 cells. Thus, the observed lycopene-induced biological effects and their associated mechanisms are encouraging and may lead to the development of a highly successful drug for the treatment of prostate cancer.

Annexin A5↗

PubMed2000

Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat.

The administration of lycopene to female rats at doses ranging from 0.001 to 0.1 g/kg b.w. per day for 2 weeks was found to alter the drug-metabolizing capacity and antioxidant status of the exposed animals. An investigation of four cytochrome P450-dependent enzymes revealed that benzyloxyresorufin O-dealkylase activity in the liver was significantly induced in a dose-dependent fashion at all lycopene doses investigated. Likewise, ethoxyresorufin O-dealkylase activity was induced, although only at the two highest lycopene concentrations tested. An investigation of selected phase 2 detoxification enzymes provided evidence that lycopene was capable of inducing hepatic quinone reductase, approximately two-fold, at doses between 0.001 and 0.05 g/kg b.w. per day, whereas no effect was observed at the remaining doses tested. Glutathione transferase, using the two substrates, 2,4-dichloronitrobenzene and 1-chloro-2, 4-dinitrobenzene, was significantly induced at the 0.1 g/kg b.w. per day dose, whereas no effect was observed at the remaining lycopene doses. Analysis of the antioxidant status of the blood compartment revealed that three out of four antioxidant enzymes were affected by lycopene treatment. The activity of superoxide dismutase was thus significantly induced at lycopene doses of 0.005 and 0.05 g/kg b.w, whereas glutathione reductase and glutathione peroxidase was only induced at the 0.005 g/kg b.w. per day dose. For all antioxidant enzymes investigated, the activities seemed to return to the control level after exerting peak induction at doses between 0.005 and 0.05 g/kg b.w. per day. The explanation for this remains unknown. The plasma concentration of lycopene at dietary levels of 0.001, 0.005, 0.05 and 0.1 g/kg b.w. per day was estimated to be 16, 32, 71 and 67 nM, which is barely within the lower range of the mean human plasma concentration of lycopene, which ranges from 70-1790 nM. Oxidative stress induced by the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and investigated by analyzing for malondialdehyde in plasma, was not found to be affected by prior lycopene exposure. The level of PhIP-DNA adducts in the liver or colon was likewise not affected by lycopene at any dose. Overall, the present study provides evidence that lycopene administered in the diet of young female rats exerts minor modifying effects toward antioxidant and drug-metabolizing enzymes involved in the protection against oxidative stress and cancer. The fact that these enzymatic activities are induced at all of these very low plasma levels, could be taken to suggest that modulation of antioxidant and drug-metabolizing enzymes may indeed be relevant to humans, which in general exhibit a plasma lycopene level several fold above the effective levels observed in this study.

Animals↗

PubMed2004

Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate.

Epidemiological evidence links consumption of lycopene, the red carotenoid of tomato, to reduced prostate cancer risk. We investigated the effect of lycopene in normal prostate tissue to gain insight into the mechanisms, by which lycopene can contribute to primary prostate cancer prevention. We supplemented young rats with 200 ppm lycopene for up to 8 wk, measured the uptake into individual prostate lobes, and analyzed lycopene-induced gene regulations in dorsal and lateral lobes after 8 wk of supplementation. Lycopene accumulated in all four prostate lobes over time, with all-trans lycopene being the predominant isoform. The lateral lobe showed a significantly higher total lycopene content than the other prostate lobes. Transcriptomics analysis revealed that lycopene treatment mildly but significantly reduced gene expression of androgen-metabolizing enzymes and androgen targets. Moreover, local expression of IGF-I was decreased in the lateral lobe. Lycopene also consistently reduced transcript levels of proinflammatory cytokines, immunoglobulins, and immunoglobulin receptors in the lateral lobe. This indicates that lycopene reduced inflammatory signals in the lateral prostate lobe. In summary, we show for the first time that lycopene reduced local prostatic androgen signaling, IGF-I expression, and basal inflammatory signals in normal prostate tissue. All of these mechanisms can contribute to the epidemiologically observed prostate cancer risk reduction by lycopene.

Androgens↗

PubMed2003

Quantitative analysis of lycopene isomers in human plasma using high-performance liquid chromatography-tandem mass spectrometry.

An analytical method for the determination of the concentrations of total lycopene and its cis and all-trans isomers in human plasma has been developed using high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). This method was based on the observation that, during negative ion atmospheric pressure chemical ionization with collision-induced dissociation, a unique fragment of m/z 467 was formed from the molecular ion of m/z 536 by elimination of a terminal isoprene group. The use of multiple reaction monitoring facilitated the selective detection of lycopene isomers and an internal standard without interference from the isobaric carotenoids a-carotene and beta-carotene, which are also abundant in human plasma. Measurement of total lycopene was carried out using a C18 high-performance liquid chromatography (HPLC) column and an isocratic mobile phase consisting of acetonitrile/methyl tert-butyl ether (95:5) so that all lycopene isomers eluted as a single chromatographic peak. all-trans-Lycopene was separated from its various cis isomers by using a C30 carotenoid column and a gradient solvent system from methanol to methyl tert-butyl ether. The effects of sample preparation and handling parameters on the stability of lycopene were evaluated such as the stability of lycopene in the HPLC autosampler and the effect of saponification upon lycopene isomerization. For example, the half-life of all-trans-lycopene in the HPLC mobile phase in the autosampler at 4 degrees C was determined to be approximately 16 h. Also, saponification of plasma samples was determined to cause lycopene degradation and isomerization so that lycopene recovery was reduced. The accuracy and interassay precision of this LC-MS-MS assay for lycopene showed a standard deviation of less than 10% over the range of 5-500 pmol injected on-column. The limit of detection was 11.2 fmol injected on-column, and the limit of quantitation was 22.8 fmol.

Anticarcinogenic Agents↗

PubMed2006

Absorption and subcellular localization of lycopene in human prostate cancer cells.

Lycopene, the red pigment of the tomato, is under investigation for the chemoprevention of prostate cancer. Because dietary lycopene has been reported to concentrate in the human prostate, its uptake and subcellular localization were investigated in the controlled environment of cell culture using the human prostate cancer cell lines LNCaP, PC-3, and DU145. After 24 hours of incubation with 1.48 micromol/L lycopene, LNCaP cells accumulated 126.6 pmol lycopene/million cells, which was 2.5 times higher than PC-3 cells and 4.5 times higher than DU145 cells. Among these cell lines, only LNCaP cells express prostate-specific antigen and fully functional androgen receptor. Levels of prostate-specific antigen secreted into the incubation medium by LNCaP cells were reduced 55% as a result of lycopene treatment at 1.48 micromol/L. The binding of lycopene to the ligand-binding domain of the human androgen receptor was carried out, but lycopene was not found to be a ligand for this receptor. Next, subcellular fractionation of LNCaP cells exposed to lycopene was carried out using centrifugation and followed by liquid chromatography-tandem mass spectrometry quantitative analysis to determine the specific cellular locations of lycopene. The majority of lycopene (55%) was localized to the nuclear membranes, followed by 26% in nuclear matrix, and then 19% in microsomes. No lycopene was detected in the cytosol. These data suggest that the rapid uptake of lycopene by LNCaP cells might be facilitated by a receptor or binding protein and that lycopene is stored selectively in the nucleus of LNCaP cells.

Anticarcinogenic Agents↗

PubMed2006

Inhibitory effects of lycopene on the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells.

Lycopene, which is the predominant carotenoid in tomatoes and tomato-based foods, may protect humans against various cancers. Effects of lycopene on the adhesion, invasion, migration, and growth of the SK-Hep1 human hepatoma cell line were investigated. Lycopene inhibited cell growth in dose-dependent manners, with growth inhibition rates of 5% and 40% at 0.1 microM and 50 microM lycopene, respectively, after 24 hrs of incubation. Similarly, after 48 hrs of incubation, lycopene at 5 microM and 10 microM decreased the cell numbers by 30% and 40%, respectively. Lycopene decreased the gelatinolytic activities of both matrix metalloproteinase (MMP)-2 and MMP-9, which were secreted from the SK-Hep1 cells. Incubation of SK-Hep1 cells with 110 microM of lycopene for 60 mins significantly inhibited cell adhesion to the Matrigel-coated substrate in a concentration-dependent manner. To study invasion, SK-Hep1 cells were grown either on Matrigel-coated Transwell membranes or in 24-well plates. The cells were treated sequentially for 24 hrs with lycopene before the start of the invasion assays. Cell growth and death were assessed under the same conditions. The invasion of SK-Hep1 cells treated with lycopene was significantly reduced to 28.3% and 61.9% of the control levels at 5 microM and 10 microM lycopene, respectively (P < 0.05). In the migration assay, lycopene-treated cells showed lower levels of migration than untreated cells. These results demonstrate the antimetastatic properties of lycopene in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells.

Anticarcinogenic Agents↗

PubMed1999

Effect of dietary lycopene on N-methylnitrosourea-induced mammary tumorigenesis.

Epidemiological studies suggest protective effects of lycopene-rich foods on several types of cancer, including prostate and gastrointestinal tract. Moreover, an inverse association between serum lycopene concentrations and several types of cancer has been reported. However, few studies have focused on breast cancer, and they have shown little association between lycopene consumption and cancer risk. In this report, we used the N-methylnitrosourea (NMU)-induced rat mammary tumor model to compare the effects of pure lycopene with a lycopene-rich tomato carotenoid oleoresin (TCO) on NMU-induced mammary tumorigenesis. Rats were fed diets supplemented with 250 and 500 ppm crystalline lycopene or TCO beginning seven days before initiation with NMU (55 days of age) to termination (18 wk after NMU). Neither pure lycopene nor lycopene in the form of a mixed carotenoid oleoresin exerted an inhibitory effect on tumor incidence, latency, multiplicity, volume, or total tumors per group compared with unsupplemented controls. Weight gains in all groups were similar. Assay of serum lycopene concentrations in lycopene-supplemented groups indicated that median levels of 7,12,60, and 87 ng/ml were attained in blood of groups supplemented with 250 and 500 ppm lycopene and 250 and 500 ppm TCO, respectively. The results of this animal study are consistent with epidemiological reports indicating that lycopene does not protect against breast cancer.

Animals↗

PubMed1999

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

Adult↗

PubMed2005

Increases in plasma lycopene concentration after consumption of tomatoes cooked with olive oil.

Lycopene is the main carotenoid in tomatoes and it has been hypothesised to be responsible for reducing the risk of some cancers and heart disease. The cooking of tomatoes with olive oil is a characteristic combination in the Southern Mediterranean diet. Previous studies have shown that the absorption of lycopene is greater from processed tomatoes than fresh tomatoes, since the processing breaks down the tomato cell matrix and makes the lycopene more available. The aim of the present study was to determine whether consumption of diced tomatoes cooked with olive oil resulted in higher plasma lycopene concentrations than consumption of diced tomatoes cooked without olive oil. Plasma lycopene concentrations were measured after 5 days on a low lycopene diet and again after a five-day dietary intervention, in healthy subjects, who consumed one meal per day of tomatoes (470 g) cooked with or without extra virgin olive oil (25 ml olive oil). There was an 82% increase in plasma trans-lycopene (P< 0.001) and a 40% in cis-lycopene (P = 0.002) concentrations in the 11 subjects who consumed tomatoes cooked in olive oil. There was no significant change in trans-lycopene (P = 0.684) and a 15% increase in cis-lycopene (P = 0.007) concentrations in 12 subjects consuming tomatoes cooked without olive oil. We conclude that the addition of olive oil to diced tomatoes during cooking greatly increases the absorption of lycopene. The results highlight the importance of cuisine (i.e how a food is prepared and consumed) in determining the bioavailability of dietary carotenoids such as lycopene.

Adolescent↗

PubMed2000

Antioxidant and pro-oxidant effects of lycopene in comparison with beta-carotene on oxidant-induced damage in Hs68 cells.

Lycopene has become a focal point in recent research following clinical trials that suggest that beta-carotene may promote lung cancer in smokers. Because lycopene only differs from beta-carotene in lacking the beta-ionone structure, and beta-carotene is known to have pro-oxidant activity in vitro, we sought to determine whether lycopene might also have pro-oxidant activity in vitro in comparison with beta-carotene. Human foreskin fibroblasts (Hs68 cells) were first enriched with 10 and 20 µM lycopene or beta-carotene for 1 hr followed by incubation with various oxidants. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) released into the medium and DNA damage was measured as formation of comet and 8-hydroxy-2'-deoxyguanosine. The results showed that lycopene at 20 µM significantly decreased levels of TBARS induced by ferric nitrilotriacetate (Fe/NTA) but enhanced levels of TBARS induced by a lipid-soluble radical generator (2,2'-azobis[2,4-dimethylvaleronitrile]; AMVN). Both the antioxidant and pro-oxidant effects of lycopene tended to be dose-dependent. beta-Carotene at 20 µM did not significantly decrease TBARS induced by Fe/NTA but significantly increased TBARS induced by AMVN. Lipid peroxidation induced by a water-soluble radical generator 2,2'-azobis(2-amidinopropane)dihydrochloride was not significantly affected by either lycopene or beta-carotene. Neither lycopene nor beta-carotene affected DNA damage or changes in cell morphology induced by any of the three oxidants tested. The present study in Hs68 cells demonstrates that lycopene can be either an antioxidant or a pro-oxidant depending on the oxidants used, and that lycopene and beta-carotene behave similarly under the in vitro oxidative conditions. Although it is unclear whether lycopene may have pro-oxidant activity in vivo, our results caution that it may be premature to undertake clinical trials with lycopene.

Journal Article↗

PubMed2005

The effect of lycopene on cell growth and oxidative DNA damage of Hep3B human hepatoma cells.

Lycopene, the predominant carotenoid in tomatoes and tomato-based foods, is reported to protect against various cancers, especially prostate cancer. We investigated the effect of lycopene on DNA damage and cell growth inhibition in the Hep3B human hepatoma cell line. Lycopene was analyzed by HPLC, and cell proliferation was determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. A final lycopene concentration of 0.1-50 microM was added to cells plated in 96-well plates. After a 24-hr incubation, cell viability was measured as absorbance at 570 nm after the MTT assay. The effects of lycopene on cell cycle progression were investigated with flow cytometry. Lycopene induced G0/G1 arrest and S phase block. Oxidative DNA damage was determined by the Comet (single-cell gel electrophoresis) assay. Lycopene inhibited cell growth in a dose-dependent manner. Cell growth was inhibited 20% at 0.2 microM lycopene and 40% at 50 microM lycopene after a 24-hr incubation. In the Comet assay, lycopene-treated cells showed less DNA damage than did placebo-treated cells. The inhibition of Hep3B cell growth in this study demonstrates the antitumor properties of lycopene.

Antioxidants↗

PubMed2001

Formation of cleavage products by autoxidation of lycopene.

The cleavage products formed by autoxidation of lycopene were evaluated in order to elucidate possible oxidation products of lycopene in biological tissues. Lycopene solubilized at 50 microM in toluene, aqueous Tween 40, or liposomal suspension was oxidized by incubating at 37 degrees C for 72 h. Among a number of oxidation products formed, eight products in the carbonyl compound fraction were identified as 3,7,11 -trimethyl-2,4,6,10-dodecatetraen-1-al, 6,10,14-trimethyl-3,5,7,9,13-pentadecapentaen-2-one, acycloretinal, apo-14'-lycopenal, apo-12'-lycopenal, apo-10'-lycopenal, apo-8'-lycopenal, and apo-6'-lycopenal. These correspond to a series of products formed by cleavage in the respective 11 conjugated double bonds of lycopene. The maximal formation of acycloretinal was 135 nM in toluene, 49 nM in aqueous Tween 40, and 64 nM in liposomal suspension. Acycloretinoic acid was also formed by autoxidation of lycopene, although its formation was lower in the aqueous media than in toluene. The pig liver homogenate had the ability to convert acycloretinal to acycloretinoic acid, comparable to the conversion of all-transretinal to all-trans-retinoic acid. These results suggest that lycopene might be cleaved to a series of apolycopenals and short-chain carbonyl compounds under the oxidative conditions in biological tissues and that acycloretinal is further enzymatically converted to acycloretinoic acid.

Animals↗