Lycopene Metabolism, Bioavailability and Immunomodulatory Effects: Comparison
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Lycopene is a carotenoid found commonly in fruits and vegetables such as tomatoes, pink grapefruit and watermelons with non-provitamin A activity. It is the compound responsible for the red coloration of the fruits. It shares the same molecular mass and chemical formula with beta-carotene, but lycopene is an open-polyene chain which lacks the β-ionone ring structure found in beta-carotene. 

  • lycopene
  • tomatoes
  • cancer
  • immune system
  • inflammation

1. Introduction

Lycopene is a carotenoid found commonly in fruits and vegetables such as tomatoes, pink grapefruit and watermelons with non-provitamin A activity. It is the compound responsible for the red coloration of the fruits. It shares the same molecular mass and chemical formula with beta-carotene, but lycopene is an open-polyene chain which lacks the β-ionone ring structure found in beta-carotene. Lycopene is a highly unsaturated hydrocarbon which is able to undergo cis-trans isomerization under induction by light, thermal or chemical reactions. Most of the lycopene found in nature, from existing plant are predominantly in trans-configuration, which is more thermodynamically stable than its cis-counterpart [11][12]. Years of research managed to identify some of the metabolites of lycopene found in human body, which could depict an idea of the metabolism of lycopene in human. Some of the known metabolites of lycopene which were detected in plasma of humans include apo-8′-lycopenal, apo-10′-lycopenal, apo-10′-lycopenoic acid and apo-10′-lycopenol [13]. Apo-8′-lycopenal and apo-10′-lycopenoic acid were the metabolites found to possess anti-cancer activity, despite being a degraded fragments of lycopene[14][15] (Figure 1). Such observation could reflect the potential of lycopene in anti-cancer as its bioactivity is considered robust as metabolic catabolism would not nullify its effect.
Molecules 26 03888 g001
Figure 1. Chemical structure of lycopene and its metabolites with reported anti-cancer property. (a) Lycopene, (b) Apo-8′-lycopenal, (c) Apo-10′-lycopenoic acid.
Lycopene was known to be able to suppress cancerous cell proliferation, migration, invasion and adhesion activity in cell culture studies. Such suppression was often observed with changes of cancer-related gene expression and relief of oxidative stress. In general, lycopene could suppress the expression of MMP-2, MMP-7, MMP-9, Sp1, IGF-1R, VEGF while increasing E-cadherin stabilization, connexin 43, nm23-H1, TIMP-1 and TIMP-2 levels [15][16][17][18][19][20][21][22]. One of pathways involved in the anti-cancer property exhibited by lycopene was associated with its ability to regulate apoptosis-related protein and gene expression such as caspase-3, caspase-8, Bax levels and Bax:Bcl-2 and Bcl-xL among cancerous cells [23][24][25][26]. 

2. Metabolism and Bioavailability of Lycopene

The metabolism of lycopene is a complicated process, whereby it has to be released from the food matrix, emulsified and solubilized into micelles before absorption could occur as it is lipid soluble. Absorption of lycopene could occur either by passive diffusion or via SR-B1 transporter and CD36 surface membrane glycoprotein found in the small intestine. The absorption process is tightly regulated by intestine-specific homeobox (ISX) transcription factor and dependent on both intestinal β-carotene 15,15′-oxygenase (BCO1) and SR-B1 expression. After lycopene uptake by the small intestine, it will undergo isomerization from all-trans configuration to 5-cis lycopene and 13-cis lycopene, to be cleaved by carotene-9′,10′ monooxygenase (BCO2) to produce apo-10′-lycopenal. Apo-10′-lycopenal would then either be oxidized to apo-10′-lycopenoic acid or reduced to apo-10′-lycopenol. The metabolites mentioned above would later be packaged into chylomicrons and transported to the lymphatic system, liver and other peripheral tissues [27]. There are several factors which were found to be able to affect the bioavailability of lycopene from food. The release of lycopene from the plant itself is one of the determining factors of bioavailability while significant food processing also did find to improve the bioavailability of lycopene. It was proposed that the act of maceration could break down the plant cell walls and thus, leading to weakening of the bond between lycopene and the plant cell tissue matrix [28]. Some research suggested thermal processing could cause isomerization of naturally occurring all trans lycopene to cis lycopene, which is more easily oxidized and bioavailable towards humans [29]. Due to the fact that lycopene is highly lipophilic, consumption of lycopene with a certain amount of fats would greatly increase uptake rather than plain consumption as oil may improve absorption of lycopene by tissues [30]. However, it is recommended to avoid consumption of lycopene concurrently with high dietary fiber intake as several types of dietary fiber were found to be able to reduce the bioavailability of lycopene [31].

3. Immunomodulatory Effects of Lycopene

The earliest evidence came in 2004 when lycopene was able to modulate dendritic cell response by downregulation of CD80, CD86 and MHC II molecules expression, which are the common protein found on surface of dendritic cells. In vivo experiment further revealed that the effect of lycopene could be extended to decreased stimulation of T cells, accompanied by reduced expression of IL-2 and IL-12, the key stimulators of T cells. It was suggested that such effect was a result of MAPK/ERK signaling pathway inhibition (ERK1/2, p38, JNK) and reduced transcription of NF-κB. These evidences gave a direction whereby lycopene could suppress the maturation of murine dendritic cells and cell-mediated response under stimulation of LPS [98]. Mast cells are a type of granulocytes commonly known to be involved in allergic reaction and anaphylaxis. It plays a major role in inflammation as mast cell degranulation could release mediators or compounds which trigger an inflammatory response. Lycopene pretreatment with basophilic leukemia cell line suppressed mast cell degranulation but such activity was most probably not a direct result of lycopene cellular uptake as there was no correlation found between cellular carotenoids content and anti-degranulation activity. This suggests that the effect of lycopene in immune system modulation is not as simple as absorption and execution and it could be a result from a complicated network consisted of simultaneous activation of various immunomodulatory pathways [99]. In barrow and gilt finishing pigs, 0, 12.5, 25, 37.5, 50 mg/kg of lycopene administration followed by immunization using 1 mg BSA caused increased lymphocyte concentration and anti-BSA IgG, reduced neutrophil concentration and eosinophil while causing no change in basophil and monocyte [100]. Changes in lymphocyte concentration could be an indicator of activation of cell-mediated or humoral immune response and thus, lycopene was proposed to be able to influence immune response and the production of antigen-specific antibodies. One study provided a lead whereby lycopene could activate the immune system, especially adaptive immunity in the process of eradicating cancerous cells. In this experiment, lycopene managed to enhance IFNβ, IFNγ, IRF1, IRF7, CXCL9, CXCL10 while suppressing IL-4, IL-10, DMNT3a, methylation of IRF1, IRF7 promoters and most importantly, the tumor volume. Increment of CD4+/CD8+ T cells ratio, percentage of IFNγ+/CD8+ T cell, percentage of perforin+/CD8+ T cell and percentage of granzyme B+/CD8+ T cell were reported, accompanied by no significant change in DNMT1 and DNMT3b [69]. Compiling these evidences depicted that lycopene could enhance activation and differentiation of T cells and T helper cells Th1/Th2 drift via suppression of IL-4 and upregulation of IFNγ, most probably by its ability to modulate cytokines, chemokines and interferons. Interferons had been known to be a central regulator for anti-tumor immunity whereby it had both anti-tumor and pro-tumor activity. In anti-tumor activity, interferons can increase antigenicity of tumor cells by upregulation of MH class I molecules and increase cytotoxic activity of both NK cells and cytotoxic T cells [101]. Suppression of DNMT3A could suppress DNA methylation of IRF1 and IRF7 promoters and thereby permitting transcription [102]. IRF1 was reported to be antioncogenic due to its ability to mediate apoptosis via induction of caspase-1, upregulation of caspase-8 and suppression of CDKs and survivin [103] while IRF7 was able to increase NK cell cytotoxic activity on cancerous cells via upregulation of IFNβ and inhibit bone metastasis [104]. 

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