A Comprehensive Monograph on Lycopene (DB11231): Chemical Profile, Biological Activity, and Clinical Evidence

1.0 Executive Summary

Lycopene is a naturally occurring tetraterpene carotenoid, a lipophilic pigment responsible for the characteristic red color of tomatoes, watermelon, and other fruits. Chemically identified by the formula $C_{40}H_{56}$ and CAS number 502-65-8, it exists predominantly in the all-trans isomeric form in nature, though numerous cis-isomers are formed during processing and are prevalent in human plasma. As a non-provitamin A carotenoid, its biological significance stems not from vitamin activity but from its potent antioxidant and anti-inflammatory properties. Its unique structure, featuring 11 conjugated double bonds, makes it one of the most effective quenchers of singlet oxygen and other reactive oxygen species (ROS) among dietary carotenoids.

The biological mechanisms of lycopene are multifaceted, extending beyond simple antioxidant defense. Evidence indicates that it modulates key cellular pathways involved in inflammation, proliferation, and intercellular communication. It has been shown to suppress pro-inflammatory cytokines, interfere with growth factor signaling, induce cell cycle arrest in cancer cells, and restore gap junctional communication—a process often lost during carcinogenesis. This complex bioactivity forms the basis for its investigation in the prevention of chronic diseases.

A substantial body of observational evidence links higher dietary intake and, more significantly, higher circulating blood levels of lycopene with a reduced risk of certain cancers and cardiovascular diseases. Meta-analyses of prospective cohort studies suggest a modest reduction in overall cancer risk and a more pronounced reduction in cancer-related mortality, with the strongest associations observed for lung cancer. For cardiovascular health, observational data consistently point to a protective effect, though results from randomized controlled intervention trials have been inconsistent, likely due to variations in study design, dosage, and the formulation of lycopene used.

Industrially, lycopene is produced either through solvent-based or supercritical fluid extraction from tomato processing byproducts—an effective example of agro-industrial waste valorization—or via fermentation using the fungus Blakeslea trispora. It is widely used in the nutraceutical industry as a dietary supplement and in the food industry as a natural red colorant.

The global regulatory landscape for lycopene is fragmented. In the United States, it is regulated primarily as a food color additive (21 CFR 73.585) and a dietary supplement, with the FDA permitting only highly qualified health claims. In the European Union, it is an authorized food additive (E 160d) with a strictly defined Acceptable Daily Intake (ADI) of 0.5 mg/kg body weight, with regulatory concern focused on potential over-exposure from all dietary sources combined. In Australia, products containing lycopene are regulated as complementary medicines. This report provides a comprehensive synthesis of the chemical, biological, clinical, and regulatory aspects of lycopene, highlighting key areas of scientific consensus and identifying critical directions for future research.

2.0 Chemical Identity and Physicochemical Properties

2.1 Nomenclature and Identification Codes

The precise identification of a chemical entity is fundamental to scientific discourse. Lycopene is known by a variety of systematic names, synonyms, and registry codes across different chemical, regulatory, and commercial databases.

• Generic Name: Lycopene [1]
• Systematic IUPAC Name: (all-E)-2,6,10,14,19,23,27,31-Octamethyl-2,6,8,10,12,14,16,18,20,22,24,26,30-dotriacontatridecaene [2]
• CAS Registry Number: 502-65-8 [1]
• DrugBank Accession Number: DB11231 [1]
• Synonyms and Other Codes: This compound is also referred to as $\psi,\psi$-Carotene, all-trans-Lycopene, trans-Lycopene, C.I. 75125, NSC-407322, Lycopene 7, and Tomat-O-Red. Regulatory and food industry codes include E-160D(III) (Europe), FEMA NO. 4110 (Flavor and Extract Manufacturers Association), and INS NO.160D(III) (International Numbering System for Food Additives). The FDA Unique Ingredient Identifier (UNII) is SB0N2N0WV6.[1]

2.2 Molecular Structure, Formula, and Stereoisomerism

Lycopene's structure is central to its chemical properties and biological function. It is a symmetrical, acyclic tetraterpene assembled from eight isoprene units, composed solely of carbon and hydrogen.[1]

• Chemical Formula: $C_{40}H_{56}$ [1]
• Molecular Weight: Values from various sources are highly consistent, reported as 536.87 g/mol, 536.888 g·mol−1, or 536.9 g/mol.[2]
• Chemical Class: Lycopene is classified within the kingdom of organic compounds, superclass of lipids and lipid-like molecules, and class of prenol lipids. Its direct parent class is carotenes, which are unsaturated hydrocarbons characterized by a long, branched alkyl chain linking two end-groups.[1]
• Stereoisomerism: The long polyene chain of lycopene, containing 11 conjugated and two non-conjugated double bonds, allows for a vast number of geometric isomers. Theoretically, 1056 cis-trans configurations are possible.[1] Despite this potential complexity, the all-trans isomer is the most thermodynamically stable and is the predominant form found in natural food sources like fresh tomatoes, where its long, linear shape is responsible for the molecule's ability to form crystalline aggregates and impart a deep red color.[1] Exposure to heat, light, or certain chemical conditions can induce isomerization to various cis-isomers, such as 5-cis, 7-cis, 9-cis, 11-cis, 13-cis, and 15-cis.[8] This structural shift from a linear to a bent shape has profound implications for bioavailability and biological function. While the all-trans form dominates the diet, various cis-isomers constitute over 60% of the total lycopene concentration found in human blood, yet the specific biological effects of these individual isomers remain largely uninvestigated.[8] This discrepancy between the primary dietary form and the primary circulating forms suggests that isomerization during food processing and in vivo metabolism is a critical, yet poorly understood, determinant of lycopene's ultimate health effects.

2.3 Physical and Chemical Properties

The physicochemical properties of lycopene dictate its stability during processing and storage, its solubility in various media, and its mechanism of absorption in the human body. Its pronounced lipophilicity is a defining characteristic that influences nearly every aspect of its journey from plant to human tissue.

• Appearance: In its pure form, lycopene is a deep red, crystalline solid.[5] Commercial preparations, such as tomato extract, typically appear as a dark-red, viscous liquid or oleoresin.[11]
• Solubility: Lycopene is hydrophobic and thus insoluble in water. It is soluble in nonpolar organic solvents such as chloroform (approximately 3 mg/ml), carbon disulfide, tetrahydrofuran (THF), and ether, and is sparingly soluble in hexane (1 g/L at 14 °C) and vegetable oils. Its solubility in polar solvents like ethanol and acetone is partial to poor.[6] This fat-solubility is a critical factor for both industrial extraction processes, which rely on organic solvents or lipid-friendly supercritical fluids, and for human digestion, which requires the presence of dietary fats for efficient absorption.
• Melting Point: Reported melting points are 175 °C and 177 °C.[7]
• Stability: Lycopene is stable for at least two years when stored under inert gas at -80°C.[5] However, it is susceptible to oxidative degradation and isomerization when exposed to light, oxygen, and heat, which can compromise its color and biological activity.[8]

Property	Value	Source(s)
Generic Name	Lycopene	1
CAS Number	502-65-8	1
DrugBank ID	DB11231	1
Molecular Formula	$C_{40}H_{56}$	1
Molecular Weight	536.87 - 536.9 g/mol	2
Appearance	Deep red crystalline solid	5
Melting Point	175 - 177 °C	7
Solubility in Water	Insoluble	8
Solubility (Organic)	Soluble in chloroform, CS2, THF, ether; Sparingly soluble in hexane, ethanol, acetone	6
Predominant Natural Isomer	all-trans	1
Table 2.1: Summary of Identifiers and Physicochemical Properties of Lycopene.

3.0 Natural Occurrence, Biosynthesis, and Dietary Sources

3.1 Role in Photosynthetic Organisms

In the biological systems of plants, algae, and other photosynthetic organisms, lycopene serves not as a final product but as a pivotal intermediate in the complex biosynthetic pathway of carotenoids.[8] Its primary role is as a precursor to other vital pigments, most notably beta-carotene (a pro-vitamin A carotenoid) and a wide array of xanthophylls.[8] These downstream carotenoids are essential for photosynthesis, where they function in light-harvesting complexes, and for photoprotection, where they dissipate excess light energy and neutralize harmful reactive oxygen species generated during the photosynthetic process.[8] Lycopene itself contributes to these functions, and its accumulation is responsible for the vibrant red and orange pigmentation of many fruits and vegetables.[8]

3.2 Biochemical Synthesis Pathways

The biosynthesis of lycopene is a highly conserved enzymatic process in plants and prokaryotic cyanobacteria.[8] The pathway begins with the precursor mevalonic acid, which is converted into dimethylallyl pyrophosphate. This molecule is then condensed with three molecules of its isomer, isopentenyl pyrophosphate, to yield the 20-carbon geranylgeranyl pyrophosphate (GGPP). In a critical tail-to-tail condensation reaction, two molecules of GGPP are joined to form phytoene, a 40-carbon molecule. This step represents the first committed stage in carotenoid biosynthesis. Phytoene subsequently undergoes a series of enzymatic desaturation steps, which introduce the conjugated double bonds characteristic of the polyene chain, ultimately yielding lycopene.[8] At this biosynthetic crossroads, the enzyme lycopene cyclase can act upon the two terminal isoprene groups of the lycopene molecule, catalyzing their cyclization to form the beta-ionone rings of beta-carotene.[8] The characteristic red color of ripe tomatoes is a direct result of the transcriptional down-regulation of the gene encoding lycopene cyclase, which causes lycopene to accumulate in high concentrations rather than being converted to beta-carotene.[14] This genetic particularity provides humans with a dietary source of a potent antioxidant that functions independently of the vitamin A pathway.

3.3 Primary Food Sources and Factors Affecting Content

Lycopene is the pigment that imparts the red to pink hues seen in a variety of common foods.[1]

• Major Dietary Sources: While present in many fruits, the predominant source of lycopene in the human diet, particularly in Western countries, is the tomato (Lycopersicon esculentum) and its derivative products. Tomato-based foods such as ketchup, tomato paste, sauces, and juices account for over 85% of the average dietary intake of lycopene.[8] Other significant natural sources include watermelon, pink grapefruit, pink guava, papaya, rosehip, gac fruit, and autumn olive.[1]
• Factors Influencing Content: The concentration of lycopene in natural sources is not static. In tomatoes, for instance, the content varies significantly depending on the specific cultivar and increases substantially as the fruit ripens.[8]
• The Impact of Food Processing: A notable and somewhat counter-intuitive characteristic of lycopene is the effect of processing on its nutritional value. Unlike many heat-labile nutrients, such as vitamin C, the bioavailability of lycopene is significantly enhanced by thermal and mechanical processing. Cooking, crushing, and canning disrupt the robust cell walls of the tomato and dissociate the crystalline aggregates of lycopene within the plant's chromoplasts.[8] This liberation from the food matrix makes the lycopene more accessible for absorption in the human gut. Consequently, processed products like tomato paste can have up to four times the bioavailable lycopene content of fresh, raw tomatoes.[8] This phenomenon, where processing enhances nutritional value, has significant implications for dietary recommendations and the food industry, positioning cooked and processed tomato products as superior sources of this bioactive compound.

4.0 Human Pharmacokinetics: Bioavailability and Disposition

4.1 Absorption and the Impact of the Food Matrix

Lycopene is classified as a non-essential nutrient for humans, as there is no defined deficiency state associated with its absence.[1] Its absorption from the gastrointestinal tract is a complex and relatively inefficient process, heavily influenced by its physicochemical properties and the composition of the food matrix in which it is consumed.

• Mechanism of Absorption: As a highly lipophilic molecule, lycopene is insoluble in the aqueous environment of the gut. Its absorption is contingent upon its incorporation into mixed micelles, which are formed with the aid of bile salts and dietary fats.[8] These micelles transport the lycopene to the surface of the intestinal enterocytes, where it can be absorbed. The overall absorption efficiency is estimated to be between 10% and 30% of the ingested amount, with the remainder being excreted in the feces.[17]
• Factors Enhancing Bioavailability: The bioavailability of lycopene is significantly enhanced by factors that facilitate its release from the food matrix and its solubilization in fat. Thermal processing (cooking) and mechanical disruption (crushing, pureeing) are highly effective at breaking down plant cell walls, thereby increasing the accessibility of lycopene.[8] The co-ingestion of dietary fats is crucial; consuming lycopene-rich foods with oils, such as in spaghetti sauce or pizza, markedly improves its assimilation.[8] Consequently, oil-based lycopene supplements may offer greater bioavailability than lycopene from unprocessed food sources.[8] Furthermore, the isomerization of the native all-trans lycopene to cis-isomers, which occurs during heating, also improves bioavailability, as the bent structure of cis-isomers is less prone to aggregation and more easily incorporated into micelles.[18]
• Factors Inhibiting Bioavailability: Conversely, certain dietary components can hinder lycopene absorption. Large, soluble fiber molecules, such as pectins, can interfere with micelle formation and reduce absorption efficiency.[18] Additionally, lycopene competes for absorption with other carotenoids, including beta-carotene and lutein, likely because they share common transport mechanisms within the enterocyte.[19] The presence of calcium has also been noted to reduce absorption.[19] This complex interplay of dietary factors means that the effective dose of lycopene absorbed by the body is not merely a function of the amount ingested but is heavily modulated by the composition of the entire meal. This variability could be a significant confounding factor in clinical studies and may help explain some of the inconsistent results observed in intervention trials.

4.2 Distribution and Tissue Accumulation

Following absorption into the enterocytes, lycopene is packaged into chylomicrons and released into the lymphatic system before entering the bloodstream. In circulation, it is transported by various classes of lipoproteins and distributed throughout the body.[11]

• Primary Accumulation Sites: Due to its lipophilic nature, lycopene preferentially accumulates in tissues with high lipid content. The primary storage depots in the human body are the liver, adrenal glands, and testes.[11] Significant concentrations are also found in adipose tissue, kidneys, and lungs.[20] The preferential accumulation in specific organs, such as the prostate, provides a strong pharmacokinetic rationale for the targeted biological effects observed in those tissues. The ability to achieve a high local concentration in the prostate, for example, may allow lycopene to exert a more potent local antioxidant or cell-regulatory effect compared to tissues where it is less concentrated, potentially explaining the extensive research focus on lycopene and prostate health.[20]
• Factors Influencing Distribution: The extent of tissue accumulation is influenced by a range of physiological and lifestyle factors, including age, body mass index (BMI), overall health of the gastrointestinal tract, and habitual dietary patterns.[18]

4.3 Metabolism and Excretion

The metabolic fate of lycopene in humans is not yet fully understood, though it is clear that the parent molecule undergoes enzymatic cleavage. It is increasingly believed that the biological effects attributed to lycopene may be mediated not only by the intact molecule but also by its various metabolic derivatives.[16]

• Metabolism: The primary enzymes involved in carotenoid metabolism are the carotenoid cleavage oxygenases, BCO1 and BCO2. These enzymes can cleave the lycopene molecule at various points along its polyene chain, leading to the formation of a range of smaller, more polar metabolites. These derivatives include apo-lycopenals, apo-lycopenols, and apo-lycopenoic acids.[16] These metabolites may possess their own unique biological activities, contributing to the overall health effects observed after lycopene consumption.
• Excretion: As noted, unabsorbed dietary lycopene is eliminated from the body via the feces.[17] The pathways for the excretion of absorbed lycopene and its metabolites are less well-defined but are presumed to involve biliary excretion into the gut and subsequent fecal elimination, as well as potential renal clearance of smaller, water-soluble metabolites.

5.0 Core Mechanisms of Biological Action

The health-promoting effects of lycopene are attributed to a diverse array of biological mechanisms. While its role as a potent antioxidant is the most widely recognized, emerging evidence reveals a more sophisticated profile as a modulator of critical cellular signaling pathways involved in inflammation, growth, and intercellular communication.

5.1 Antioxidant and Reactive Oxygen Species (ROS) Scavenging Activity

The primary and most extensively documented mechanism of action for lycopene is its exceptional antioxidant capacity. This activity is a direct consequence of its unique molecular structure, which features a system of 11 conjugated double bonds that can effectively delocalize electron energy and neutralize free radicals.[22]

• Potency and Specificity: Lycopene is recognized as the most potent scavenger of singlet oxygen ($^{1}O_2$), a highly reactive and damaging form of oxygen, among all common dietary carotenoids.[1] Its physical quenching rate constant for singlet oxygen is reported to be twice that of $\beta$-carotene and up to 100 times greater than that of $\alpha$-tocopherol (vitamin E).[22] In addition to singlet oxygen, lycopene can directly scavenge a broad spectrum of other reactive oxygen species (ROS) and reactive nitrogen species (RNS), including hydroxyl radicals ($\cdot$OH), peroxynitrite (ONOO-), and hydrogen peroxide ($H_2O_2$).[22] By neutralizing these species, lycopene protects vital cellular macromolecules—including lipids, proteins, and DNA—from oxidative damage, a key initiating factor in the pathogenesis of many chronic diseases.[14]

5.2 Anti-inflammatory Pathways

Chronic, low-grade inflammation is a key driver of diseases such as cancer and cardiovascular disease. Lycopene has demonstrated significant anti-inflammatory properties that are distinct from its direct antioxidant effects. It actively modulates inflammatory signaling cascades, primarily by inhibiting the activation of the master inflammatory transcription factor, nuclear factor-kappa B (NF-$\kappa$B).[24] By preventing NF-$\kappa$B activation, lycopene suppresses the downstream expression of a suite of pro-inflammatory genes, leading to reduced production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-$\alpha$), interleukin-6 (IL-6), and interleukin-1 beta (IL-1$\beta$).[11]

5.3 Modulation of Cellular Growth, Proliferation, and Communication

Perhaps the most sophisticated of its mechanisms are those related to the direct regulation of cellular behavior. These non-antioxidant actions provide a compelling rationale for lycopene's potential role in cancer prevention and therapy.

• Cell Cycle Regulation: At physiological concentrations achievable through diet, lycopene has been shown to inhibit the proliferation of various cancer cell lines. It achieves this by interfering with growth factor receptor signaling pathways (such as the insulin-like growth factor 1 (IGF-1) pathway) and by inducing cell cycle arrest, typically at the G0/G1 checkpoint, thereby preventing uncontrolled cell division.[14] This effect is notably achieved without inducing toxicity or apoptosis in normal, healthy cells.[14]
• Induction of Apoptosis: While cytostatic to normal cells, lycopene can selectively induce apoptosis (programmed cell death) in cancerous cells, a critical mechanism for eliminating malignant cells from the body.[20]
• Restoration of Intercellular Communication: A particularly elegant mechanism involves the restoration of gap junctional intercellular communication (GJC). Many tumor cells lose the ability to communicate with their neighbors, a hallmark of malignant transformation. Lycopene has been found to upregulate the expression of the gene encoding connexin 43, a key protein component of gap junctions.[14] By rebuilding these communication channels, lycopene can help re-establish normal tissue homeostasis and suppress the proliferative advantage of tumor cells.[14] This reframes lycopene from a passive antioxidant "shield" to an active "manager" of cellular communities, providing a powerful mechanism for its observed anti-carcinogenic effects.
• Pro-oxidant Duality: An intriguing aspect of lycopene's activity in the context of cancer is its potential to act as a pro-oxidant. While it functions as an antioxidant in healthy tissues, it may selectively induce oxidative stress within cancer cells, which often have a compromised redox balance. This pro-oxidant effect can push malignant cells past a threshold of oxidative damage, triggering apoptosis and contributing to their elimination.[18] This dual, context-dependent functionality would make it an ideal chemopreventive agent, protecting healthy tissue while promoting the destruction of nascent tumors.

6.0 Clinical Research and Health Implications: An Evidence-Based Review

The potential health benefits of lycopene, suggested by its potent biological mechanisms, have been the subject of extensive clinical and epidemiological investigation. The primary areas of focus have been cardiovascular disease and cancer, where oxidative stress and chronic inflammation are key pathogenic drivers. This section provides a critical review of the evidence from major meta-analyses and clinical trials.

6.1 Cardiovascular Disease: A Critical Review of Meta-Analyses

The evidence linking lycopene to cardiovascular health presents a classic dichotomy often seen in nutrition research: strong, consistent associations in observational studies versus more equivocal results from intervention trials.

• Observational Evidence: A comprehensive 2017 meta-analysis of 14 observational studies demonstrated a statistically significant inverse association between lycopene exposure and the risk of cardiovascular diseases (CVD).[26] The pooled analysis revealed that individuals with higher lycopene exposure had a 17% lower risk of CVD (pooled risk ratio of 0.83). This protective association held for both coronary heart disease (RR: 0.87) and stroke (RR: 0.83) when assessing dietary intake. The association was even stronger in studies using blood lycopene levels as the biomarker of exposure, particularly for stroke risk (RR: 0.65), underscoring the importance of absorption and bioavailability over mere dietary intake.[26]
• Intervention Trials: Randomized controlled trials (RCTs) examining the effects of lycopene supplementation on cardiovascular risk factors have yielded mixed results. A 2020 systematic review reported conflicting findings on the ability of lycopene to improve blood pressure and lipid profiles.[19] In contrast, a more recent 2023 review of 13 RCTs concluded that lycopene interventions could produce significant reductions in blood pressure, particularly in hypertensive individuals, and lead to favorable alterations in lipid profiles.[28] Some studies suggest mechanisms such as reduced arterial stiffness, lower levels of pro-inflammatory cytokines, and improvements in endothelial function.[15] The inconsistency across intervention trials is likely attributable to significant heterogeneity in study design, including wide variations in lycopene dosage (ranging from 1.44 to 75 mg/day), the form of lycopene used (e.g., supplements vs. tomato paste), the duration of the intervention, and the baseline health status of the participants.[27] This suggests that the benefits of lycopene may be more pronounced over the long term as part of a consistent dietary pattern, an effect that is difficult to capture in shorter-duration RCTs.

Study/Author	Year	No. of Studies / Participants	Key Outcome(s)	Result (Risk Ratio, 95% CI)	Key Conclusion
Song et al.	2017	14 observational studies	Overall CVD Risk	0.83 (0.76–0.90)	Higher lycopene exposure is inversely associated with a lower risk of CVD.
			Coronary Heart Disease (Diet)	0.87 (0.76–0.98)	Association is significant for CHD and stroke.
			Stroke (Diet)	0.83 (0.69–0.96)
			Stroke (Biomarker)	0.65 (0.42–0.87)
Cheng et al.	2020	43 intervention studies (Systematic Review)	Blood Pressure, Lipids	Conflicting findings; meta-analysis showed no significant differences.	High variability in study design, dose, and delivery mode leads to conflicting results.
Shidfar et al.	2023	13 RCTs / 385 participants (Systematic Review)	Blood Pressure, Lipids, Oxidative Stress	Significant BP reductions, favorable lipid alterations, mitigation of oxidative stress.	Shows potential in managing cardiovascular risk factors, but more rigorous studies are needed.
Table 6.1: Synopsis of Major Meta-Analyses on Lycopene and Cardiovascular Disease Outcomes.

6.2 Oncology: Evaluating the Association with Cancer Risk and Mortality

Lycopene's potential role in cancer prevention is its most researched application. Recent large-scale meta-analyses have provided a clearer, albeit nuanced, picture of its association with cancer risk and mortality.

• Overall Cancer Risk and Mortality: A landmark 2025 meta-analysis encompassing 121 prospective studies and nearly 2.7 million participants found that high blood levels of lycopene were associated with an 11% reduction in overall cancer risk (RR: 0.89).[30] The association with dietary intake was weaker but still significant, showing a 5% risk reduction (RR: 0.95).[32] The link was substantially stronger for cancer-related mortality: high tomato intake was associated with an 11% lower risk, high lycopene intake with a 16% lower risk, and high blood lycopene levels with up to a 24% reduction in cancer mortality.[30]
• Prostate Cancer: This has historically been the cancer most strongly linked to lycopene. Numerous epidemiological studies have suggested a protective effect.[25] However, the large 2025 meta-analysis delivered a critical clarification: while higher blood levels of lycopene were associated with a 10–14% reduction in prostate cancer risk, higher dietary intake alone was not found to have a statistically significant impact.[30] This distinction highlights that individual differences in absorption and metabolism are paramount, making circulating lycopene concentration the more relevant biomarker.
• Lung Cancer: The most robust association was observed for lung cancer. The meta-analysis found that individuals with the highest blood lycopene levels had a remarkable 35% lower risk of lung cancer mortality.[30]
• Dose-Response Relationship: The analysis also identified a beneficial dose range for cancer risk reduction, suggesting that an intake of approximately 5–7 mg per day confers a protective effect, with little to no additional benefit observed for intakes exceeding 10 mg per day.[30] It is crucial to note that these findings are based on observational data and do not establish causality; however, they provide strong support for the role of lycopene-rich diets in cancer risk mitigation.

Study/Author	Year	No. of Studies / Participants	Cancer Type(s)	Key Outcome(s) & Result (Risk Ratio, 95% CI)	Key Conclusion
Balali et al. (reported in Frontiers in Nutrition)	2025	121 prospective studies / ~2.7 million	Overall Cancer	Incidence: High Blood Level: 0.89 (0.84–0.95); High Dietary Intake: 0.95 (0.92–0.98)	Higher blood levels of lycopene are a stronger predictor of reduced cancer risk and mortality than dietary intake alone.
				Mortality: High Blood Level: 0.76 (0.60–0.98); High Dietary Intake: 0.84 (0.81–0.86)
			Prostate Cancer	Incidence: High Blood Level: ~10-14% reduction; High Dietary Intake: Not Significant
			Lung Cancer	Mortality: High Blood Level: 0.65 (0.45–0.94)	The strongest association is seen for lung cancer mortality.
Table 6.2: Synopsis of Major Meta-Analyses on Lycopene and Cancer Risk/Mortality.

6.3 Evidence in Other Investigated Conditions

Beyond cardiovascular disease and cancer, lycopene has been investigated for a range of other health conditions.

• Oral Lichen Planus: Lycopene has been studied as a potential treatment for oral lichen planus, an inflammatory condition of the mouth. Completed Phase 2 (NCT00656214) and Phase 4 (NCT02587117) clinical trials have evaluated its efficacy, in some cases comparing it directly to the corticosteroid prednisolone, suggesting its potential as a therapeutic agent for this condition.[34]
• Male Fertility: Preclinical and clinical evidence suggests that lycopene may improve male fertility. Oxidative stress is a major contributor to sperm damage, leading to reduced motility and DNA fragmentation. By accumulating in reproductive tissues and exerting its potent antioxidant effects, lycopene has been linked to improvements in sperm motility and morphology.[17]
• Dermatological Photoprotection: Lycopene accumulates in human skin and is thought to provide a degree of protection against damage induced by ultraviolet (UV) radiation.[5] This "dietary photoprotection" is attributed to its ability to neutralize ROS generated in the skin upon UV exposure, thereby mitigating inflammation and cellular damage.[5]

7.0 Industrial Production and Commercial Applications

The growing consumer demand for natural ingredients and the mounting scientific interest in its health benefits have driven the development of sophisticated industrial methods for producing lycopene. Production is dominated by two distinct pathways: extraction from agricultural sources and biosynthesis via microbial fermentation.

7.1 Extraction Technologies from Tomato Byproducts

The primary industrial source of natural lycopene is the tomato, specifically the waste stream from the tomato processing industry. This approach represents an exemplary model of a circular economy, transforming low-value agro-industrial byproducts (pomace, which consists of skins and seeds) into a high-value nutraceutical and food ingredient.[36]

• Solvent Extraction: This is the conventional and most cost-effective method. It involves using organic solvents, such as ethyl acetate or mixtures of hexane and acetone, to extract the lipophilic lycopene from dried and ground tomato pomace.[36] To improve efficiency, a pretreatment step using enzymes like pectinase or cellulase can be employed. These enzymes degrade the plant cell wall matrix, liberating the lycopene and enhancing the extraction yield.[39] While effective, this method raises concerns regarding potential residual solvents in the final product and the environmental impact of solvent use.[39]
• Supercritical Fluid Extraction (SFE): This advanced "green" technology offers an alternative to organic solvents. It most commonly utilizes carbon dioxide ($CO_2$) heated and pressurized to a supercritical state, where it exhibits properties of both a liquid and a gas. Supercritical $CO_2$ acts as a highly effective nonpolar solvent for lycopene, and after extraction, it can be easily removed by depressurization, leaving a solvent-free product.[36] Other gases, such as ethane, have also been shown to be effective.[37] The selectivity and efficiency of SFE can be fine-tuned by adjusting pressure, temperature, and the use of co-solvents (e.g., ethanol).[37] The primary disadvantage of SFE is the high capital investment required for the specialized equipment, which limits its application compared to conventional solvent extraction.[36]

7.2 Microbial Biosynthesis via Blakeslea trispora Fermentation

An alternative to agricultural extraction is the biotechnological production of lycopene using the filamentous fungus Blakeslea trispora. This microorganism is a known industrial producer of carotenoids and offers a highly controlled and scalable production platform.[42]

• Fermentation Process: The process involves the co-fermentation or "mated fermentation" of two sexually distinct mating types (+ and -) of the fungus in a nutrient-rich medium.[44] This sexual interaction stimulates the production of signaling molecules called trisporic acids, which in turn strongly upregulate the entire carotenoid biosynthesis pathway.[44] To maximize the accumulation of lycopene specifically, the process can be modified in two ways: by using mutant strains of B. trispora that have a genetic block in the lycopene cyclase enzyme, or by adding chemical inhibitors of this enzyme (such as piperidine or creatinine) to the fermentation broth. Both methods prevent the conversion of lycopene into its downstream product, $\beta$-carotene, causing it to accumulate to high levels.[44]
• Downstream Processing: Following fermentation, the fungal biomass is harvested, and the lycopene is extracted using food-grade solvents like isopropanol and isobutyl acetate. The final product is then purified by crystallization and filtration.[12] This method allows for the production of a high-purity, bio-identical lycopene that is not dependent on agricultural harvests, though it may not align with consumer preferences for "plant-derived" ingredients.

7.3 Applications in the Food and Nutraceutical Industries

Lycopene's vibrant color and documented health benefits have led to its widespread use in two major commercial sectors.

• Dietary Supplements: Lycopene is a popular ingredient in the nutraceutical market, where it is sold as a standalone supplement or as part of multi-ingredient formulations.[1] It is typically marketed for general antioxidant support and for targeted health concerns such as prostate health, cardiovascular wellness, and skin health.[16] To overcome its poor water solubility and enhance absorption, supplements are most often formulated in oil-based softgels.[8]
• Food Colorant: As a natural and stable red pigment, tomato lycopene extract and concentrate are approved for use as food colorants in many regions worldwide.[1] They provide shades ranging from yellow to red and are used in a diverse array of food products, including non-alcoholic beverages, baked goods, breakfast cereals, dairy products, soups, and salad dressings.[11]

8.0 Safety, Toxicology, and Drug Interactions

8.1 Toxicological Profile and Adverse Effects

Lycopene has an excellent safety profile, supported by its long history of consumption in the human diet and formal toxicological studies. It is designated as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration for its use in food.[25]

• Toxicity: Acute, sub-chronic, and chronic toxicity studies in animal models have not revealed any significant adverse effects, even at extremely high doses of up to 3 g/kg of body weight per day.[21] No severe side effects have been reported in human clinical trials.[49]
• Adverse Effects: The most commonly reported and well-documented side effect of excessive lycopene consumption is lycopenemia (also known as lycopenodermia). This is a benign and reversible condition characterized by a yellowish-orange discoloration of the skin, particularly the palms and soles, caused by the deposition of the pigment in the stratum corneum.[8] The condition resolves upon reduction of lycopene intake. In rare cases of intolerance, individuals may experience mild gastrointestinal symptoms, such as nausea, diarrhea, gas, or stomach cramps.[8]

8.2 Dosage Considerations and Recommended Intake

There is no official Recommended Daily Allowance (RDA) for lycopene, as it is not considered an essential nutrient. However, various guidelines and studied dosages have been established.

• Studied Doses: Doses used in human clinical trials have varied widely, ranging from as low as 2 mg per day to as high as 75 mg per day, and have been administered safely for periods of up to six months.[19]
• Suggested Health-Promoting Intake: Based on epidemiological data, some researchers suggest a daily intake of 5–10 mg is required to achieve potential health benefits.[21] Meta-analyses focusing on cancer risk have identified an optimal beneficial range of 5–7 mg per day, with diminishing returns for intakes above 10 mg/day.[30]
• Regulatory Upper Limits: The European Food Safety Authority (EFSA) has established a conservative Acceptable Daily Intake (ADI) for lycopene from all dietary sources (natural, fortified foods, supplements, and food colorants) of 0.5 mg per kilogram of body weight per day.[53] For a 70 kg adult, this corresponds to 35 mg per day. This ADI creates a potential regulatory challenge, as high consumers of lycopene-rich foods, particularly children, could exceed this limit, especially with the addition of fortified products and supplements.[54]

8.3 Clinically Significant Drug and Nutrient Interactions

While lycopene is toxicologically safe, it is a bioactive compound with pharmacological properties that can lead to clinically significant interactions with certain medications and nutrients.

• Anticoagulant and Antiplatelet Drugs: This is the most critical interaction. Lycopene has been shown to possess mild antiplatelet (blood-thinning) properties and may inhibit blood clotting.[51] Consequently, co-administration of high-dose lycopene supplements with anticoagulant medications (e.g., warfarin), antiplatelet drugs (e.g., aspirin, clopidogrel), or nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen could theoretically increase the risk of bleeding.[8] It is recommended that individuals taking these medications consult a healthcare provider before using lycopene supplements and that supplementation be discontinued at least two weeks prior to any scheduled surgery.[19]
• Antihypertensive Drugs: Some evidence suggests that lycopene may have a modest blood pressure-lowering effect.[28] Therefore, it could have an additive effect when taken with antihypertensive medications, potentially leading to hypotension.[8]
• Nutrient-Nutrient Interactions: As discussed in the pharmacokinetics section, lycopene competes with other carotenoids, such as beta-carotene and lutein, for intestinal absorption. High doses of one carotenoid may therefore reduce the absorption of others.[19] Calcium has also been reported to decrease lycopene absorption.[19]
• Other Potential Interactions: A possible interaction with alcohol has been observed in animal models, where high-dose lycopene combined with alcohol induced the expression of the metabolic enzyme CYP2E1; however, the clinical relevance of this finding in humans is unknown.[56]

9.0 Global Regulatory Framework: A Comparative Analysis

The regulation of lycopene varies significantly across major international markets, reflecting different legislative philosophies regarding foods, supplements, and medicines. A product containing lycopene may be classified as a food colorant, a novel food, a dietary supplement, or a therapeutic good, depending on the jurisdiction. This regulatory fragmentation presents a significant challenge for the global marketing and formulation of lycopene-containing products.

9.1 United States Food and Drug Administration (FDA)

In the United States, lycopene is regulated under several different frameworks depending on its intended use.

• As a Color Additive: The primary legal status of lycopene is as a food color additive. Under Title 21 of the Code of Federal Regulations, Section 73.585 (21 CFR 73.585), "Tomato lycopene extract" and "Tomato lycopene concentrate" are permanently listed for the coloring of foods generally.[57] The regulation specifies their identity, manufacturing process (extraction with ethyl acetate), and purity specifications (e.g., $\geq$ 5.5% lycopene for extract, $\geq$ 60% for concentrate). They are exempt from batch certification and can be used in amounts consistent with Good Manufacturing Practice (GMP).[58]
• As a Dietary Supplement and Health Claims: Lycopene is legally sold as a dietary supplement, having been marketed prior to the 1994 Dietary Supplement Health and Education Act (DSHEA).[19] However, the FDA maintains a very high standard of "significant scientific agreement" for authorizing health claims that link a substance to disease risk reduction. In 2004, after reviewing petitions, the FDA concluded there was no credible evidence to support strong health claims for lycopene and the risk of most cancers. It permitted only a very limited and highly qualified health claim for tomato consumption and a potential reduced risk of prostate cancer, which must be accompanied by significant disclaimers stating the evidence is limited and inconclusive.[61]
• GRAS Status: Synthetic forms of lycopene have been the subject of several self-affirmed Generally Recognized as Safe (GRAS) notifications for use as a nutrient in various food categories, to which the FDA has issued letters of no objection.[48]

9.2 European Food Safety Authority (EFSA)

In the European Union, lycopene is regulated primarily as a food additive and a novel food, with a strong emphasis on establishing a safe upper limit for total consumption.

• As a Food Additive: Lycopene is an authorized food colorant across the EU, designated by the E number E 160d.[54] This authorization covers lycopene from various sources, including tomatoes, the fungus Blakeslea trispora, and chemical synthesis.[54]
• Acceptable Daily Intake (ADI): A key feature of the European regulatory approach is the establishment of a group ADI for lycopene from all possible dietary sources combined. EFSA's scientific panels have set this ADI at 0.5 mg per kilogram of body weight per day.[53]
• Safety and Exposure Concerns: EFSA has repeatedly expressed concern that the cumulative intake of lycopene from its natural occurrence in foods, its use as a color additive, and its addition to fortified foods and supplements may cause certain segments of the population, particularly children who are high consumers of products like flavored drinks, to exceed the ADI.[53] This has led EFSA to issue public calls for more precise data on usage levels and dietary exposure to refine its risk assessments.[64]
• Health Claims: Similar to the FDA, EFSA's Panel on Dietetic Products, Nutrition and Allergies (NDA) has reviewed proposed health claims for lycopene and concluded that the scientific evidence was insufficient to substantiate claims related to the protection of DNA, proteins, and lipids from oxidative damage or the protection of skin from UV-induced damage.[65]

9.3 Australian Therapeutic Goods Administration (TGA)

Australia regulates supplements containing lycopene under a distinct framework, classifying them as therapeutic goods (medicines) rather than foods or food additives.

• As a Therapeutic Good: Products containing lycopene as an active ingredient are regulated as complementary medicines and must be included in the Australian Register of Therapeutic Goods (ARTG).[66] These products are typically "Listed" medicines (identified by an AUST L number), which means the TGA has assessed them for quality and safety but not for efficacy.[68] The botanical source is often specified as Lycopersicon esculentum.[66] This classification subjects the manufacturing of these supplements to the same strict Code of Good Manufacturing Practice (GMP) that applies to pharmaceutical drugs, ensuring a high standard of quality control.[68]

Regulatory Body	Primary Classification	Key Regulation / Identifier	Stance on Health Claims	Key Safety / Dosage Guideline
FDA (USA)	Color Additive; Dietary Supplement	21 CFR 73.585; DSHEA	Very restrictive; only highly qualified claims with disclaimers permitted.	Use according to Good Manufacturing Practice (GMP) as a colorant. No official upper limit for supplements.
EFSA (EU)	Food Additive; Novel Food	E 160d	Unsubstantiated; claims for antioxidant and skin protection benefits not approved.	Strict Acceptable Daily Intake (ADI) of 0.5 mg/kg bw/day from all sources.
TGA (Australia)	Therapeutic Good (Complementary Medicine)	Australian Register of Therapeutic Goods (ARTG)	Permitted claims must be substantiated but are not pre-approved for efficacy by TGA for Listed medicines.	Regulated as a medicine; manufacturing must comply with pharmaceutical GMP.
Table 9.1: Comparative Overview of the Regulatory Status of Lycopene.

10.0 Synthesis and Future Directions

Lycopene is a well-characterized lipophilic carotenoid with a robust profile of biological activity, underpinned by its potent antioxidant capacity and its more nuanced role as a modulator of cellular signaling pathways. The extensive body of epidemiological research provides compelling, consistent evidence of an association between higher lycopene status and reduced risk for several chronic diseases, most notably certain cancers and cardiovascular conditions. A critical theme emerging from this evidence is the superior predictive power of circulating blood lycopene concentrations over estimated dietary intake, highlighting the pivotal role of individual pharmacokinetics—absorption, metabolism, and disposition—in determining biological effect.

This strong observational evidence, however, is met with more equivocal findings from randomized controlled intervention trials. This common discrepancy in nutrition science likely stems from several factors: the inherent difficulty of demonstrating the prevention of long-latency diseases in short-term trials, the heterogeneity in study designs and lycopene formulations, and the challenge of isolating the effect of a single nutrient from the complex, synergistic matrix of a whole food. Lycopene is likely not a pharmacological "magic bullet" but rather a key component of a long-term, disease-preventive dietary pattern.

Based on the knowledge gaps identified throughout this monograph, several key avenues for future research are proposed to clarify the role of lycopene in human health and to translate scientific findings into effective public health and clinical strategies.

• 1. Isomer-Specific Biological Research: The observation that cis-isomers predominate in human plasma while the all-trans form dominates the diet represents a critical knowledge gap. Research is urgently needed to elucidate the specific biological activities of the major cis-isomers (e.g., 5-cis, 9-cis, 13-cis). Intervention studies using purified or enriched cis-isomers are required to determine if they possess greater potency in modulating cellular pathways compared to the all-trans form, which could explain the health effects seen in populations consuming lycopene.
• 2. Biomarker-Driven Clinical Trials: Future intervention trials should shift their design paradigm from administering a fixed dose to targeting a specific, predefined serum lycopene concentration. Such a design would account for inter-individual variability in absorption and metabolism, reducing study noise and providing a clearer assessment of the dose-response relationship between circulating lycopene and clinical outcomes.
• 3. Head-to-Head Comparison of Whole Food vs. Supplements: Long-term, well-controlled clinical trials are needed to directly compare the health effects of consuming lycopene from a whole food source (e.g., standardized tomato paste) versus an equivalent dose from an isolated, purified supplement. This would help determine the extent to which other bioactive compounds in tomatoes (e.g., other carotenoids, polyphenols, vitamins) act synergistically with lycopene to produce the observed health benefits.
• 4. Investigation into Pharmacogenomics: Research into the genetic basis of lycopene pharmacokinetics is a promising frontier. Identifying genetic polymorphisms in enzymes and transporters involved in carotenoid absorption (e.g., SR-B1), cleavage (e.g., BCO1, BCO2), and transport could explain why some individuals achieve higher blood lycopene levels than others on a similar diet. This knowledge could ultimately pave the way for personalized nutritional recommendations tailored to an individual's genetic capacity to process and utilize lycopene.

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