Whole Food versus Supplement: Comparing the Clinical Evidence of Tomato Intake and Lycopene Supplementation on Cardiovascular Risk Factors^,

Abstract

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in the United States and worldwide. A link between diet and CVD is well established, with dietary modification a foundational component of CVD prevention and management. With the discovery of bioactive components beyond the essential nutrients of foods, a new era of nutritional, medical, botanical, physiologic, and analytical sciences has unfolded. The ability to identify, isolate, purify, and deliver single components has expanded the dietary supplement business and health opportunity for consumers. Lycopene is an example of a food component that has attracted attention from scientists as well as food, agriculture, and dietary supplement industries. A major question, however, is whether delivering lycopene through a supplement source is as effective as or more effective than consuming lycopene through whole food sources, specifically the tomato, which is the richest source of lycopene in the Western diet. In this review, we examined clinical trials comparing the efficacy of lycopene supplements with tomato products on intermediate CVD risk factors including oxidative stress, inflammation, endothelial function, blood pressure, and lipid metabolism. Overall, the present review highlights the need for more targeted research; however, at present, the available clinical research supports consuming tomato-based foods as a first-line approach to cardiovascular health. With the exception of blood pressure management where lycopene supplementation was favored, tomato intake provided more favorable results on cardiovascular risk endpoints than did lycopene supplementation. Indeed, future research that is well designed, clinically focused, mechanistically revealing, and relevant to human intake will undoubtedly add to the growing body of knowledge unveiling the promise of tomatoes and/or lycopene supplementation as an integral component of a heart-healthy diet.

Introduction

The consumption of a diet rich in fruits and vegetables is associated with a reduced risk of cardiovascular disease (CVD)7 (1), in part through reductions in atherosclerosis, a main underlying mechanism leading to CVD. The established pathophysiologic (risk) factors for atherosclerosis impact regulatory functions of the endothelium, promoting an unstable, lipid accumulating, and inflexible vascular environment. Components of fruits and vegetables that influence these risk factors may beneficially impact atherosclerosis, endothelial function, and therefore CVD development.

Tomatoes are well recognized for their culinary versatility and multiethnic menu presence. Tomatoes also contribute significantly to the nutritional value of the diet, providing a number of essential nutrients and other bioactive components (2). However, tomatoes and tomato-based foods are best known as a rich source of dietary lycopene. Initially, tomato and lycopene intake was linked with reductions in prostate cancer (3–5). More recently, the association between tomato and/or lycopene consumption and CVD risk reduction has gained research interest. The discovery of lycopene as a potent antioxidant in vitro is largely responsible for the initial scientific and public interest in tomatoes as a health-promoting food. However, advances in lycopene science have revealed that the biologic function of lycopene is through a variety of plausible mechanisms because its metabolic products impact a variety of cellular processes (6, 7).

There is a strong relation between tomato intake and blood concentrations of lycopene (8–10). Epidemiologic investigations have shown an inverse relation between plasma, serum, and tissue concentrations of lycopene and risk of CVD (11–15). These data led to the conjecture that lycopene is the primary reason that tomatoes are associated with favorable reductions in CVD and other health outcomes. Correspondingly, efforts to increase lycopene consumption have ranged from breeding tomatoes with higher amounts of lycopene to extracting and concentrating lycopene to be sold as a dietary supplement.

Considering the background and efforts to increase lycopene consumption, a major question that remains to be answered is whether delivering lycopene or tomato extracts rich in lycopene through a capsule is as effective as or more effective than consuming tomatoes, the primary food source of lycopene and other key nutrients. The purpose of the current review aimed to address this question relative to CVD risk by examining the available clinical trials assessing the efficacy of lycopene delivered through consumption of tomato products versus lycopene as a dietary supplement on CVD risk factors. Clinical trials were identified in Medline with PubMed searches that included the key words tomato and, or lycopene and lipids, cholesterol, blood pressure (BP), oxidative stress, antioxidant, inflammation, endothelial function, and flow mediated dilation (FMD). Clinical trials were cross-referenced against review article citations where appropriate.

The Tomato

Tomatoes are the edible fruits from the plant Solanumlycopersicum, commonly known as a tomato plant. The tomato belongs to the nightshade family. Historically, tomatoes were found in Mexico, but with the Spanish colonization of the Americas, the species and its use spread around the world. The tomato is consumed raw and as a processed ingredient in many dishes, sauces, salads, and drinks.

Tomatoes contain high quantities of vitamin C, vitamin A, fiber, and potassium along with a variety of other nutrients in lesser amounts. Potassium and fiber are 2 nutrients that have been targeted in prescriptive diets for BP and lipid management. Tomatoes also contain components to favor reduction-oxidation (redox) balance (e.g., lycopene, vitamin C, polyphenols, and phenolic acids) that reduce the risk of cellular oxidative damage, modulating cellular signaling pathways involved in inflammation and endothelial function among other cellular events. Lycopene is one of the most biologically active plant-derived compounds, and tomatoes and tomato-based foods are the richest sources of lycopene in the American diet (2). Therefore, the package of nutrients and bioactive components that tomatoes deliver suggests an important protective role of tomatoes in a heart-healthy diet.

Lycopene: Sources, Chemistry, Bioavailability, and Transport

As a supplement, lycopene is usually packaged in dark bottles to protect from light exposure, which could lead to degradation and loss of bioactivity. Lycopene is sold as a pure extract or as part of a tomato extract, such as Lyc-O-Mato(LycoRed Group). In foods, lycopene is found in watermelon and red grapefruit; however, tomatoes and tomato products represent >85% of all the dietary sources of lycopene consumed in the North American diet (16).

Lycopene is a natural red pigment synthesized by plants and microorganisms but not by animals. Lycopene is an acyclic isomer of β-carotene with no provitamin A activity. Lycopene is a highly unsaturated hydrocarbon containing 11 conjugated and 2 unconjugated double bonds (17). Because of the high number of conjugated dienes within lycopene, its potency as an effective singlet oxygen quencher is about twice that of β-carotene and ∼10 times that of vitamin E, although lycopene circulates at much lower concentrations than vitamin E, which may impact its role biologically as a radical quenching antioxidant (18, 19).

Lycopene from plant sources exists predominantly as an all-trans isomer; however, the more bioavailable form is cis-lycopene (20). The cis-isomer geometry allows for more efficient incorporation of lycopene into mixed micelles in the lumen and of the small intestine, into chylomicrons in the enterocyte, and into VLDLs by the liver (17, 21). The trans-cis isomerization occurs readily under acid conditions (22), such as in gastric juices, as well as with exposure to light and thermal energy. Cooking and processing (i.e., thermal energy) converts some of the trans-lycopene to cis-lycopene but also releases lycopene from the cell structure matrix, increasing its bioaccessibility (23, 24). Accordingly, lycopene bioavailability is greater from tomato paste and tomato purée than from raw tomatoes (25–27). Lycopene bioavailability from supplements does not appear to be different from processed tomato paste when consumed with a meal (28).

Dietary fat also enhances the bioavailability of lycopene (29, 30) by providing stimuli for bile secretion for assembly of micelles and incorporation of lipids, lycopene, and other lipophilic components. Dietary lycopene bioavailability is therefore greater after cooking or processing tomatoes and when tomato products are consumed with oil and other dietary fats as a source of dietary lipids (25–27, 29–31).

Lycopene bioavailability in supplemental form has not been as extensively studied and remains an important area for research. Cohn et al. (28) compared the bioavailability of lycopene from tomato juice, tomato paste, and a lycopene tablet, each consumed with a standardized meal. Bioavailability and plasma kinetic profiles of lycopene tablets and tomato paste were not different, although both resulted in greater lycopene bioavailability than the tomato juice, reinforcing the importance of processing and lipids for enhanced bioavailability of lycopene. Because tomatoes also contain other lipid-soluble components, such as phytoene, phytofluene, ζ-carotene, γ-carotene, β-carotene, eurosporene, and lutein, consuming processed tomatoes under these conditions would enhance absorption of several other nutrients in addition to lycopene. Hence, a distinct advantage of consuming processed tomato products over a lycopene supplement is the inclusion of additional nutrients and bioactive components in the diet—consistent with dietary recommendations to eat more fruits and vegetables. Therefore, an important unanswered question that this review aims to address is whether there is convincing scientific justification to recommend lycopene supplementation over tomato intake for reducing CVD risk.

Cardiovascular Risk Factors

Traditional risk factors for CVD include cigarette smoking, elevated BP, elevated total cholesterol (TC) and LDL cholesterol, low HDL cholesterol, type 2 diabetes, and advanced age (32, 33). Others risk factors include obesity, family history, being male, and sedentary lifestyle, although these are not a focus of this review. Although these risk factors for CVD predict up to 50% of CVD (34), it has become increasingly important to shift prevention efforts toward other risk factors, including biomarkers and intermediate markers, associated with CVD morbidity and mortality.

In this review, selected traditional (lipids and BP) and emerging (oxidative stress, inflammation, and endothelial function) risk factors will be discussed. These risk factors or markers were chosen because of the existing mechanistic evidence for a role of lycopene or tomato intake in modulating these risk factors, as well as because of sufficient clinical trial evidence to review and attempt to make conclusions. The prevailing hypothesis for lycopene’s bioactivity in the body is through its ability to act as an antioxidant. Although the “oxidative stress hypothesis” has evolved over the years, oxidative stress and inflammation are paramount in the process of CVD development, along with endothelial dysfunction and elevated BP. Therefore, oxidative stress will be reviewed first, followed by inflammation, endothelial function, BP, and finally lipid metabolism.

Oxidative Stress: Tomatoes versus Lycopene

Oxidative stress.

An increase in oxidative stress resulting in oxidative damage has been implicated in the initiation, progression, and complication of CVDs (35–38). Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) and antioxidant defenses (39, 40). Within the vessel wall, different oxidants can originate from cellular and extracellular sources, and from enzymatic and nonenzymatic pathways (41). Overproduction of ROS [or reactive nitrogen species (RNS)] occurs with aging and under various environmental challenges, such as smoking, pollution, and consumption of the Western diet (42–45). Unmanaged, ROS/RNS can cause damage to cellular components such as DNA, proteins, and lipids, resulting in impaired cellular function or mutation and/or cell death. Examples of ROS causing damaging effects within the human body include singlet oxygen (¹O₂), superoxide (O₂⁻), peroxyl radicals (ROO⁻), hydroxyl radical (HO⁻), and peroxynitrite (ONOO⁻) (46, 47). The sources of ROS in the vessel wall include excessive stimulation of NAD(P)H oxidase or from sources such as mitochondrial electron transport chain, xanthine oxidase, and uncoupled endothelial NO synthase (46, 48–52). Another source of oxidation is myeloperoxidase, which is secreted by phagocytes, including neutrophils, monocytes, and macrophages. Myeloperoxidase is an enzyme that generates hypochlorus acid (HOCl). Chlorinated biomolecules are considered to be specific markers of oxidation reactions catalyzed by myeloperoxidase (53). This system can give rise to various products, some of which are relevant to LDL oxidation. For example, the generation of free amino acid or protein-bound tyrosyl radicals may, in turn, participate in secondary oxidation reactions, including LDL oxidation (53, 54). Oxidized LDLs are integral to the conversion of macrophages into foam cells in the vessel wall: the foundation for plaque formation.

Balancing oxidative “stress.”

A paradox in metabolism is that, whereas oxygen is required for life, it is also a highly reactive molecule that can cause damage to living organisms when excessive amounts of ROS are generated or not removed or neutralized before they cause damage. The goal of the antioxidant defenses system is to strike a “balance” to achieve levels for optimal cellular function. Superoxide (O₂⁻) is among the most commonly generated ROS, which is generally dismutated immediately by superoxide dismutase (SOD) to hydrogen peroxide (H₂O₂). H₂O₂ is further degraded into H₂O by catalase or several types of peroxidases, including glutathione peroxidases and peroxiredoxin (thioredoxin peroxidases) (55). In addition to enzymatic defenses, cells also rely on nonenzymatic molecules such as ascorbic acid, carotenoids, glutathione, or polyphenols to achieve cellular redox balance. Several nonenzymatic antioxidant molecules are obtained from the diet, particularly from a diet rich in fruits and vegetables.

Lycopene is an example of a lipid-soluble (hydrophobic) compound with in vitro antioxidant properties that can be obtained from food or supplements. In general, lipid-soluble antioxidants protect cell membranes from lipid peroxidation, whereas water-soluble antioxidant molecules react with oxidants in the hydrophilic cell cytosol and blood plasma. Lycopene is lipophilic and affects lipid metabolism (56) and lipid oxidation, which are involved in atherosclerotic processes. Several investigations have studied the role of lycopene in the protection of lipids from oxidation (lipid peroxidation) and, in particular, LDLs from oxidation.

Oxidized LDLs.

Oxidized LDLs are highly atherogenic (57, 58). Oxidized LDLs, caused partially by the end products of lipid peroxidation, stimulate cholesterol accumulation and foam cell formation giving rise to fatty streaks and plaques in the arterial wall. Additionally, oxidized LDLs stimulate the synthesis of adhesion molecules by endothelial cells and induces an array of proinflammatory events, initiating as well as advancing progression and complication of vascular disease. Hence, minimizing oxidation of LDL could have significant preventative and therapeutic implications for reducing CVD risk, including risk of life-threatening events.

Ten clinical trials have reported on the effect of supplementation with lycopene (Table 1), and 17 clinical trials reported on tomato and tomato-based products as a source of lycopene (Table 2) on LDL oxidation. Lycopene supplementation ranged from 5 h (postprandial evaluation) to 12 wk of treatment. Lycopene doses ranged from 6.5 mg/d lycopene (for 8 wk) to 75 mg/d (for 1 wk). Lyc-O-Mato, which is a tomato lycopene complex containing several phytonutrients including phytoene, phytofluene, β-carotene, tocopherols, and phytosterols, in addition to lycopene, was used most frequently as the lycopene supplement. Other lycopene supplements have included extracts from tomato, synthetic lycopene beadlets, or tomato oleoresin (see Table 1). Overall, of 10 studies reporting changes in LDL oxidation, 4 reported beneficial outcomes (59–62), 1 at 5 h after consumption of lycopene with a fatty meal (61), and 3 others after 1, 3, or 8 wk of supplementation. The 1- and 3-wk interventions were effective but also included coadministration with fish oil (62) or used a relatively high dose (75 mg/d for 1 wk) (59), which may have accounted for faster improvements. Engelhard et al. (60) reported decreases in LDL oxidation after 8 wk of treatment using 15 mg/d lycopene supplementation; however, in a dose-response study (0–30 mg/d, including an intermediate dose of 15 mg lycopene) for 8 wk, changes in LDL oxidation status were not observed (63). Longer duration trials at similar daily dosages did not improve LDL oxidation status.

TABLE 1.

Clinical trials examining lycopene supplementation on oxidation of LDLs¹

Reference	Year	First author	n	Participants	Study design	Length of Treatment	Lycopene source	Treatments	Lycopene dose	LDL oxidation
									mg/d
(59)	1998	Agarwal	19	M, F	Crossover	1 wk each	Lyc-O-Mato	Placebo	0	↓
				OW	4 treatments			Lyc-O-Mato	75
				25–40 y				Spaghetti sauce	39.2
								Tomato juice	50.4
(139)	2000	Carroll	51	M, F	Parallel	12 wk	Lyc-O-Pen	Placebo	0	—
				60–83 y	3 treatments			Carotene	0
				Double-blind	Lycopene			13.3
(61)	2000	Fuhrman	4	30–45 y	Postprandial	0–5 h	Tomato oleoresin	Lycopene with fatty meal, 1200 kcal	30	↓ at 5 h
					1 treatment
					BC
(140)	2001	Hininger	175	M	Parallel	12 wk	Tomato extract	Placebo	0	—
					4 treatments			Lycopene	15
								β-Carotene	0
								Lutein	0
(141)	2002	Olmedilla	400	M, F	Parallel	20 wk	Tomato extract	Vitamin E	0	—
				HW	Sequential			Lycopene (or other carotenoids)	13.3
				25–45 y	n=100/treatment			Vitamin E + lycopene (or other treatments)	13.3
(62)	2003	Kiokias	32	M, F	Crossover	3 wk each	Lyc-O-Mato	Fish oil	0	↓
				HW	2 treatments			Fish oil + carotenoid extract with Lyc-O-Mato	4.5
				32 ± 11 y	Double-blind
(60)	2006	Engelhard	31	Grade 1 hypertension	Sequential	16 wk: 4 wk placebo, 8 wk treatment, 4 wk placebo	Lyc-O-Mato	Placebo	0	↓
				30–70 y	2 treatments			Lyc-O-Mato with meals	15
				No medications
(63)	2008	Devaraj	77	M, F	Parallel	8 wk	Lycopene beadlet, all trans	Placebo	0	—
				OW	4 treatments			Lycopene	6.5
				>40 y	Double-blind			Dose-response	15
									30
(108)	2009	Markovits	16	OB, HW	1 treatment	4 wk	Lyc-O-Mato	Lycopene	30	—
					BC
(74)	2012	Thies	225	M,F	Parallel 3 txt	12-wk	Lycopene	Low Tomato, LT	0	—
				HW,OW,OB		4-wk run-in		LT + Lycopene	10
				40–65 y				High Tomato	32–50

¹BC, baseline control; HW, healthy weight for height based on standard BMI criteria; OB, obese BMI; OW, overweight BMI; ↓, decrease or reduction; —, neutral or no effect compared to control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

TABLE 2.

Clinical trials examining tomato and tomato products on oxidation of LDLs¹

Reference	Year	First author	n	Participants	Study design	Length of treatment	Tomato source	Treatments	Daily dose	Lycopene dose	LDL oxidation
										mg/d
(59)	1998	Agarwal	19	Healthy M, F	Crossover	1 wk each	Tomato juice	Placebo	0 mg	0	↓
					4 treatments			Lyc-O-Mato	1.2 g	75
				OW			Spaghetti sauce	Spaghetti sauce	126 g	39.2
				25–40 y				Tomato juice	540 mL	50.4
(67)	1998	Steinberg	39	Smokers	Crossover	4 wk	Tomato juice	Tomato juice	237 mL	Unspecified	—
				M, F	2 treatments			Tomato juice + vitamins C and E and β-carotene	237 mL
				HW, OW		4-wk placebo run-in
				28 ± 3 y
(142)	1999	Dugas	2	Healthy, 22–45 y	2 treatments	3 wk	Tomato juice	Tomato juice	12 ounces	34	—
					LDL enrichment study			β-Carotene (4 wk)		0
(66)	1999	Sutherland	15	Renal transplant recipients	Crossover	4 wk	Tomato juice	Synthetic orange drink	NI	NI	—
				M, F	2 treatments			Tomato juice
(68)	2000	Bub	23	Healthy M	Sequential	2 wk each	Tomato juice	Depletion	0 g	0	↓
					4 treatments	2-wk run-in carotenoid depletion		Tomato juice	330 mL	40
				27–40 y	BC			Carrot juice	330 mL	0
								Dried spinach	10 g	0
(64)	2000	Chopra	34	Healthy F	Crossover	7 d each	Tomato/watermelon	Spinach/mango	300 g (2:1)	0	↓ Nonsmokers
				Smokers	2 treatments			Tomato/watermelon	300 g (2:1)	>40
				Nonsmokers		8 d depletion run-in					— Smokers
				24–52 y
(65)	2000	Upritchard	57	Diabetes (T2D)	Parallel	4 wk	Tomato juice	Placebo	0 mL	0	↓
				M, F	4 treatments	4-wk placebo run-in		Tomato juice	500 mL	44
				50–75 y					(250 mL × 2)
								Vitamin E	800 IU	0
								Vitamin C	500 mg	0
(70)	2003	Hadley	60	Healthy M, F	Parallel	15 d	Tomato soup	Tomato soup (condensed)	300 mL	35	↓
					3 treatments			Tomato soup (RTE)	320 mL	23
				>40 y	BC	1-wk run-in (lycopene free)	V8 juice	V8 juice	340 mL	25
(72)	2003	Visioli	12	Healthy F	1 treatment	3 wk	Tomato	Tomato		8	↓
				HW	BC		Raw	Raw	100 g × 2/wk
				22–38 y		1 wk run-in (carotenoid poor)	Sauce	Sauce	60 g × 3/wk
							Paste	Paste	15 g × 2/wk
(73)	2004	Briviba	22	Healthy M	Crossover	2 wk each	Tomato juice	Carrot juice	330 mL	0	↓ (P = 0.08)
					2 treatments	2-wk carotenoid depletion run-in, 2-wk washout		Tomato juice	330 mL	37
										mg/d
(86)	2004	Rao	17	Healthy M, F	1 treatments	4 wk	Tomato products	Tomato products: sauce, paste, soup, juice, purée, ketchup	30–454 mL	29–33	—
					BC	2-wk lycopene depletion washout/run-in
(77)	2005	Bub	22	Healthy M	Crossover	2 wk each	Tomato juice	Carrot juice	330 mL	0	—
					2 treatments	2-wk carotenoid depletion run-in, 2-wk washout		Tomato juice	330 mL	37
(71)	2007	Silaste	21	Healthy M, F	Sequential	3 wk	Tomato juice	Low-tomato diet	None	27	↓
				HW	2 treatments			High-tomato diet	400 mL
				20–49 y	BC	2-wk baseline, 3-wk low-tomato diet	Ketchup	Tomato juice, ketchup with all main meals	30 g
(131)	2011	Shidfar	32	Diabetes (T2D)	1 treatment	8 wk	Tomato, raw	Raw tomato	200 g at lunch	NI	—
				M	BC
				40–60 y	2-wk nontomato run-in
(69)	2012	Burton-Freeman	25	Healthy M, F	Crossover	1 d	Tomato paste	Control meal	0 g	0	↓
				HW	Postprandial	6 h		Tomato meal	94 g	27
				27 ± 8 y	2 treatments
(74)	2012	Thies	225	M, F	Parallel	12 wk	Tomato products	Low tomato	Limited	0	—
				HW, OW, OB	3 treatments	4-wk run-in		Low tomato + lycopene	10 mg	10
				40–65 y				High tomato	Points system	32–50
(110)	2013	Ghavipour	106	Healthy F	Parallel	20 d	Tomato juice	Water	110 mL × 3	0	—
				OW, OB	2 treatments			Tomato juice	110 mL × 3 with meals	37
				20–40 y

¹BC, baseline control; HW, healthy weight for height based on standard BMI criteria; NI, not indicated; OB, obese BMI; OW, overweight BMI; RTE, ready to eat; T2D, type 2 diabetes; ↓, decrease or reduction; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

One distinct difference among trials was the heterogeneity among study populations selected; Engelhard et al. (60) recruited participants with stage 1 hypertension, whereas other studies generally included healthy individuals of varying ages with differences in body weight ranging from healthy weight to obese. There were no other apparent associations between body weight (as assessed by BMI) and changes in LDL oxidation after follow-up.

In comparison to lycopene supplementation, which showed improvements in measures of LDL oxidation status in 40% (4 of 10) of the reported studies, consumption of tomatoes and/or tomato products resulted in the following: 1) significant improvements in LDL oxidation status in 7 of 17 studies (an eighth study reported a trend for improvement, P = 0.08), 2) mixed results in 2 of 17 studies [one study showed improvements in nonsmokers, but not in smokers (64); and the second study conducted in smokers only showed improvements on one out of two measures of LDL oxidation (65)], and 3) 7 of the 17 studies reported no observable differences in LDL oxidation status after tomato/tomato product intervention. Interventions ranged in duration [6 h (postprandial) to 12 wk], the tomato products consumed (paste, soup, juice, sauce, purée, ketchup), and dose of lycopene from varying tomato sources (from 8 to ∼50 mg/d).

Participants were generally healthy with the exception of 1 study that recruited individuals with type 2 diabetes (65) and 1 other study included renal transplant patients (66). Two studies included smokers (64, 67), in whom tomato juice consumption did not improve resistance to LDL oxidation, even when directly compared with nonsmokers in the same study (64, 67). One interpretation of the results is that a greater amount of tomato products delivering a higher dose of antioxidants may be required to overcome the stress imposed by smoking, because addition of vitamin C, vitamin E, and β-carotene to tomato juice resulted in improvements in the resistance of LDLs to oxidation (67).

The evaluation of protective activity for tomato products in nonsmokers who were otherwise healthy indicated significant improvements in oxidized LDL status in 7 of 13 studies (59, 64, 68–72), with an eighth study reporting nonsignificant (P = 0.08) improvements in LDL oxidation status (73).

There was no clear “optimal” dose or amount of tomato product to consume. After standardizing treatment interventions on the basis of lycopene content of products, improvement in resistance to LDL oxidation was observed after consuming a variety of tomato products in amounts that delivered as low as an average of 8 mg of lycopene/d for 3 wk (72), incorporating 100 g raw tomato and 15 g tomato paste twice per week, respectively, and 60 g tomato sauce thrice per week to 50.4 mg of lycopene/d for 1 wk (59), 126 g spaghetti sauce (39.2 mg lycopene), or 540 mL tomato juice (50.4 mg lycopene). By comparison, Thies et al. (74) provided a variety of commercially available tomato products to disease-free middle-aged adults delivering up to 50 mg lycopene/d for 12 wk but did not observe improved LDL oxidation status.

Overall, there seems to be a modest benefit in consuming tomato products versus taking a lycopene supplement daily on measures of oxidized LDLs; however, the benefit appears to be confined to relatively healthy, nonsmoking individuals. Research remains sparse among “at risk” individuals, and particularly among the growing population of those with metabolic syndrome and diabetes. One of 2 studies reported improved LDL oxidation status in individuals with type 2 diabetes after consumption of tomato juice (65). Future studies are required to examine dose/amount effects and requirements for decreasing oxidation of LDLs in individuals with CVD risk factors.

Oxidative stress and antioxidant capacity.

The development of reliable methods for assessing oxidative stress status and quantifying antioxidant capacity (AOX) of foods/supplements remains a subject of interest and intense research in hopes to match the AOX of foods with biologic AOX in vivo. AOX is the ability of a compound to reduce pro-oxidants (75). Methods for measuring AOX of a food or biologic sample have been classified as inhibition methods involving reactive species (76). The most commonly used methods include oxygen radical absorbance capacity (ORAC), ferric reducing ability of plasma [also known as ferric-reducing antioxidant power (FRAP)], Trolox equivalent antioxidant capacity (TEAC), and total peroxyl radical-trapping antioxidant parameter (TRAP). The ORAC and FRAP methods are probably the most established measures of AOX but still have their limitations. Antioxidant reactions are typically chain reactions that involve initiation, propagation, branching, and termination of free radicals. From a mechanistic standpoint, each AOX assay provides somewhat different information relative to their action in the sense of antioxidants inhibiting formation of ROS (initiation) or impacting propagation and branching steps and thereby breaking radical chain sequences, and unfortunately, often yield incongruent results. None of the assays provide specific insight to protection from damage, such as to lipids, DNA, or protein or upregulating gene expression of endogenous antioxidant defenses. Therefore, studies using these assay methodologies for AOX status to illustrate the associated health effects of tomato intake or lycopene supplementation should be interpreted with caution.

Comparing nonspecific plasma or serum AOX results after lycopene supplementation and tomato product consumption revealed no improvements in AOX after lycopene supplementation (0 of 4 indicated improvements) by using ORAC, TRAP, or TEAC methods. After tomato product consumption, only 2 studies out of 10 showed improvements in plasma or serum AOX. Changes in nonspecific measures of AOX do not always correlate with specific indicators of stress or damage to biologic components. For example, Kiokias and Gordon (62) reported no change in ORAC after a 3-wk intervention with fish oil plus lycopene supplement but did report decreases in LDL oxidation and DNA damage. Similarly, a decrease in lipid oxidation products was observed without change in AOX of plasma (68, 72, 77, 78); and conversely, with increased AOX (i.e., TRAP) from tomato juice consumption (79), no change in lipid peroxidation (i.e., TBARS) was evident. Consequently, the utility of these nonspecific measures of oxidative status has been questioned.

Specific oxidative stress and damage indicators.

When ROS are produced at a rate that exceeds antioxidant defense capabilities, oxidative stress can result. Sequentially, these free radicals start chain reactions that can damage major constituents in the cells, such as protein, lipid, and DNA resulting in functional impairments, mutations, and possibly cell death. Measuring specific changes in cellular components may be a better indicator of protection by dietary constituents, including lycopene and tomatoes.

As shown in Table 3, lycopene supplementation had a consistent lack of effect on changes in lipid peroxidation (i.e., TBARS, malondialdehyde, F₂-isoprostanes) or protein oxidation (i.e., protein thiols), with only 2 trials reporting decreased serum TBARS or malondialdehyde (80, 81). Notably, lycopene supplementation reduced DNA oxidative damage in 5 of 8 studies (62, 63, 82–84), although responses were inconsistent relative to the use of the comet assay with and without peroxide/oxidative stress induction (82, 83, 85).

TABLE 3.

Clinical trials examining lycopene supplementation on markers of oxidative stress/damage¹

										AOX
Reference	Year	First author	n	Participants	Study design	Length of treatment	Lycopene source	Treatments	Lycopene dose	Nonspecific	Lipid, DNA, protein	Defense
									mg/d
(81)	1998	Rao	19	M, F	Crossover	1 wk each	Lyc-O-Mato	Placebo	0		TBARS (↓)
				OB, NW	4 treatments			Lyc-O-Mato	75		Thiols (—)
				25–40 y				Spaghetti sauce	39.2		DNA damage (—)
								Tomato juice	50.4		(8-OH-dG)
(143)	1999	Böhm	22	F	Parallel	6 wk	Lyc-O-Mato	Lyc-O-Mato	5	TEAC (—)
				HW	3 treatments			Tomato	5	TRAP (—)
				20–27 y				Tomato juice with dinner	5
(140)	2001	Hininger	175	M	Parallel	12 wk	Tomato extract	Placebo	0			Plasma and RBCs
					4 treatments			Lycopene	15			Se-GSH-Px (—)
								β-Carotene	0			Cu, Zn-SOD (—)
								Lutein	0			GSH (—)
												GSSG (—)
												SH (—)
(141)	2002	Olmedilla	400	M, F	Parallel	12 wk	Tomato extract	Vitamin E	0			Plasma and RBCs
				HW	Sequential			Lycopene (or other carotenoids or placebo)	13.3			Se-GSH-Px (—)
				25–45 y	n=100/treatment			Vitamin E + lycopene	13.3			Cu, Zn-SOD (—)
												GSH (—)
												GSSG (—)
												SH–
(62)	2003	Kiokias	32	M, F	Crossover	3 wk each	Lyc-O-Mato	Fish oil	0	ORAC (—)	DNA damage (↓)
				HW	2 treatments			Fish oil + carotenoid extract with Lyc-O-Mato	4.5
				32 ± 11 y	Double-blind						(8-OH-dG)
(73)	2004	Briviba	55	Smokers and nonsmokers	Parallel	2 wk	Lyc-O-Mato	Placebo	0		DNA damage (—) (comet)
				M	2 treatments			Lyc-O-Mato after dinner	14.6
				32 ± 12 y	Double-blind
(82)	2005	Porrini	26	M, F	Crossover	26 d	Lyc-O-Mato	Placebo	0	,	DNADamage (↓) (comet with Ox stress)
				HW	2 treatments			Lyc-O-Mato	5.7
				26 ± 3 y	Double-blind
(60)	2006	Engelhard	31	Grade 1 hypertension	Sequential	16-wk: 4 wk placebo, 8 wk treatment,4 wk placebo	Lyc-O-Mato	Placebo	15		GSH thiols (—)	GPx activity (—)
				30–70 y	2 treatments			Lyc-O-Mato with meals
				No medications
(80)	2006	Misra	41	Healthy, postmenopausal F	Parallel	6 mo	LycoRed	HRT	0		GSH thiols (↑)
				HW, OW	2 treatments			LycoRed	4		MDA (↓)
				46 y
									mg/d
(85)	2006	Riso	26	M, F	Crossover	26 d	Lyc-O-Mato	Placebo	0		DNA damage (—) (comet)
				HW	2 treatments			Lyc-O-Mato	5.7
				26 ± 3 y	Double-blind						F2 Iso U (—)
(83)	2006	Zhao	37	Postmenopausal F	Parallel	56 d	Synthetic lycopene	Placebo	0		DNA damage (↓) (comet)
				50–70 y	5 treatments			Mixed carotenoids	4
					Double-blind			Single carotenoid	12
								Lycopene		DNA damage (—) (comet with Ox stress)
								Lutein
β-Carotene
(79)	2007	Shen	24	Volunteers, Undefined	Parallel	6 wk	Lycopene, food-grade	Tomatoes, raw	∼40	TRAP (—)	TBARS (—)
				HW	3 treatments			Tomato juice
				18–23 y	BC			Lycopene
								Lunch and dinner
(107)	2008	Denniss	27	M, F (2:1)	Postprandial	1 wk	Lyc-O-Mato	Lycopene	80		MDA (—)
				HW, OW	1 treatment			Challenge meals
				18–26 y	BC			HFm: breakfast,
								1107 kcal, 60 g fat
LFm: breakfast, 1110 kcal, 243 g carbohydrate
(63)	2008	Devaraj	77	M, F	Parallel	8 wk	Lycopene beadlet, all trans	Placebo	0		MDA, HNE (—)
				OW	4 treatments			Lycopene	6.5	F2 Iso U (—)
				>40 y	Double-blind			Dose-response	15	DNA damage (↓) (comet) at 30 mg dose
											30
			DNA damage (↓) (8-OH-dG), at 30 mg
(136)	2010	Talvas	30	Healthy M	Parallel	1 wk each	Lycopene	Placebo	0	ORAC (—)	F2 Iso U (—)
				2 treatments	Lycopene	16
				OW	Crossover	1 wk each		Yellow tomato paste	0
50–70 y	2 treatments	Red tomato paste	16
(84)	2011	Kim	126	Healthy M	Parallel	8 wk each	Lycopene	Placebo	0		DNA damage (↓) (comet)	SOD activity (↑)
					3 treatments			Lycopene	6
	Lycopene	15
	2013	McEneny	54	M, F	Parallel	12 wk	Lycopene extract	Low tomato	0			PON-1 activity (↑)
HW, OW, OB				3 treatments	Low tomato + lycopene	10
40–65 y	4-wk run-in	High tomato	32–50

¹AOX, antioxidant capacity; BC, baseline control; Cu, Zn-SOD, superoxide dismutase with copper or zinc; F₂ Iso U, F₂ isoprostane urine; GPx, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; HFm, high-fat meal; HNE, 4-hydroxynonenal or 4-hydroxy-2-nonenal; HW, healthy weight for height based on standard BMI criteria; LFm, low-fat meal; MDA, malondialdehyde; NI, not indicated; OB, obese BMI; OW, overweight BMI; Ox, oxidative; PON-1, paraoxinase 1; Se-GSH-Px, selenium cofactor for glutathione peroxidase; SH, thiol; SOD, superoxide dismutase; TEAC, Trolox equivalent antioxidant capacity; TRAP, total peroxyl radical trapping; 8-OH-dG, 8-hydroxydeoxyguanosine; ↓, decrease or reduction; ↑, increase; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

On the other hand, 10 of 17 studies testing tomato products reported decreases in endpoints related to lipid peroxidation. One study also evaluated protein oxidation and found an increase in protein thiols (86). Four of 6 studies (87–90) also showed significant decreases in DNA oxidation, with a fifth showing a marginal effect (P = 0.07) (91) (Table 4). Of the 6 studies measuring changes in endogenous antioxidant defenses, only 2 (92, 93) reported increased antioxidant enzymes along with decreases in malondialdehyde.

TABLE 4.

Clinical trials examining tomato and tomato products on markers of oxidative stress/damage¹

											AOX
Reference	Year	First author	n	Participants	Study design	Length of treatment	Tomato source	Treatments	Daily dose	Lycopene dose	Nonspecific	Lipid, DNA protein	Defense
										mg/d
(87)	1997	Pool-Zobel	23	Healthy	Sequential	2 wk	Tomato juice	Depletion	0 g	0		DNA damage (↓) (comet)
				27–40 y	4 treatments	Tomato juice		330 mL	40
					BC	2-wk carotenoid depletion run-in		Carrot juice	330 mL	0
Dried spinach	10 g	0
(67)	1998	Steinberg	39	Smokers	Crossover	4 wk	Tomato juice	Tomato juice (placebo)	237 mL	NI	TRAP (—)
				M, F	2 treatments	4-wk placebo run-in
				HW, OW				Tomato juice + vitamins C and E, β-carotene	237 mL
28 ± 3 y
(91)	1999	Rehman	5	Healthy M, F (1:4)	Single bolus	1 dose	Fresh tomato	Fresh tomatoes	8 g/kg (360–728 g)	NI		DNA damage (↓)
				1 treatment
				HW	BC						8-OH-dG (↓P = 0.07)
27 ± 7 y
(89)	1999	Riso	10	Healthy F	Crossover	21 d each	Tomato purée	Tomato-free diet	0 g	0		DNA Ox damage (↓) (comet with Ox stress)
2 treatments	1-wk run-in	Tomato purée diet	60 g	16.5
(66)	1999	Sutherland	15	Renal transplantrecipients	Crossover	4 wk	Tomato juice	Synthetic orange drink	NI	NI		TBARS (—)
				2 treatments	Tomato juice
M, F
(68)	2000	Bub	23	Healthy M	Sequential	2 wk each	Tomato juice	Carotenoid depletion	0 g	0	FRAP (—)	TBARS (↓)	GPx (—)
				4 treatments	Tomato juice	330 mL		40	SOD (—)
				27–40 y	BC	2-wk carotenoid depletion run-in		Carrot juice	330 mL	0			CAT (—)
								Dried spinach	10 g	0			GR (—)
													tGSH (—)
GSSG (—)
(88)	2000	Porrini	9	Healthy F	1 treatment	14 d	Tomato purée	Tomato purée	25 g	7		DNA damage (↓) (comet with Ox stress)
				BC
					HW	1-wk carotenoid depletion/ throughout		Unconsumed,uncooked
∼25 y	At lunch with pasta, olive oil
(72)	2003	Visioli	12	Healthy F	1 treatment	3 wk	Tomato	Tomato	100 g ×2/wk	8	TAC of plasma (—)	F2 Iso (↓)
				BC	Raw	Raw
					HW	1-wk run-in (carotenoid poor)	Sauce	Sauce	60 g ×3/wk
22–38 y	Paste	Paste	15 g ×2/wk
(73)	2004	Briviba	22	Healthy M	Crossover	2 wk each	Tomato juice	Carrot juice	330 mL	0		MDA (—)
					2 treatments	2-wk carotenoid depletion run-in		Tomato juice	330 mL	37
2-wk washout
										mg/d
(135)	2004	Collins	10	Healthy M,F	Crossover	3 wk each	Tomato juice	No tomatoes	0 g juice	0	FRAP (—)	MDA (—)	GPx (—)
				Tomato juice	122 g juice ×2/d	18.4
				HW, OW, OB	3 treatments	2-wk run-in, 4-wk washout		Watermelon juice	260 g juice ×3/d with meals	20.1
35–68 y
(86)	2004	Rao	17	Healthy M, F	1 treatment	4 wk	Tomato products	Tomato products: sauce, paste, soup, juice, purée, ketchup	30–454 mL	29–33	TAC (↑)	MDA (serum) (↓)
					BC	2-wk lycopene depletion washout/run-in						MDA (U) (—)
												MDA (LDL) (—)
Protein thiols (serum) (↑)
(90)	2004	Riso	12	Healthy F	1 treatment	3 wk	Tomato	Tomato	100 g, 2×/wk	8		MDA (—)
				BC		Raw	Raw	DNA Ox damage (↓) (comet with Ox stress)
				HW		1-wk run-in (carotenoid poor)	Sauce		Sauce		60 g ×3/wk
22–38 y			Paste	Paste	15 g ×2/wk
(144)	2004	Tyssandier	20	Healthy F	1 treatment	3 wk	Tomato purée	Tomato purée	96 g	14	TAC (—)
				BC	TAC (↓) (after washout)
						HW					3-wk tomato washout/run-in
20–40 y
(77)	2005	Bub	22	Healthy M	Crossover	2 wk each	Tomato juice	Carrot juice	330 mL	0		MDA (↓) (QR/RR genotype)	PON-1 (—)
					2 treatments	2-wk carotenoid depletion run-in		Tomato juice	330 mL	37
2-wk washout
(92)	2006	Bose	30	Diabetes (T2D)	1 treatment	60 d (n = 30 of T2D only)	Tomato	Tomatoes (cooked)	200 g (cooked)			MDA (↓)	SOD (↑)
					BC					GSH-Px (↑)
										GR (↑)
	GSH (↑)
(134)	2006	Madrid	17	Healthy M, F	1 treatment	7 d	Tomato juice	Tomato juice	4 mL/kg	∼18 per 70 kg BW	TRAP (—)		CAT (—)
BC	SOD (—)
(109)	2006	Sánchez-Moreno	12	Healthy M, F	1 treatment	14 d	Tomato soup	Tomato-based soup	500 mL	NI		F2 Iso (↓)
				BC	Uric acid (↓)
									∼22 y		250 mL ×2/d
Morning, evening
										mg/d
(93)	2007	Bose	20	CHD	1 treatment	60 d	Tomato	Tomatoes (cooked)	200 g (cooked)	∼25		MDA (↓)	SOD (↑)
					BC						GSH-Px (↑)
											GR (↑)
	GSH (↑)
(79)	2007	Shen	24	HW	Parallel	6 wk	Tomato juice	Small raw tomatoes	500 g	∼40	TRAP (↑) (TJ)	TBARS (—)
				18–23 y	3 treatments		Tomato, raw	Tomato juice	600 mL
					BC			Food-grade lycopene	600 mL
Lunch and dinner
(78)	2008	Jacob	24	Healthy M, F	Parallel	2 wk	Tomato juice	Tomato juice	250 mL ×2/d	21	TEAC (—)	F2 Iso U (—)
				2 treatments	Tomato juice + vitamin C	250 mL ×2/d		21	FRAP (—)	Uric acid (—)
						HW				2-wk run-in	am, pm	PCO (—)
19–27 y	TBARS (↓)
(145)	2009	Burri	21	Healthy M, F	Crossover	1 wk each	Tomato chili	Tangerine tomato chili	300 g chili	9.63		TBARS (↓) (tangerine tomato)
2 treatments	1-wk washouts	Red tomato chili	300 g chili	27.7
(146)	2009	Lee	10	Healthy M	Crossover	48 h	Tomato	Rice, olive oil	0 g	1		F2 Iso P (—)
					2 treatments			Tomato, rice, olive oil	150 g	30	F2 Iso U (↓)
					8-OH-dG (—)
					1-wk run-in						HETEs (—)
											Urate (—)
Allantoin (—)
(136)	2010	Talvas	30	Healthy	Crossover	1 wk each	Tomato paste	Yellow tomato	200 g	0	FRAP (—)	F2 Iso U (—)
				OW	2 treatments			Red tomato	200 g	16	ORAC (—)
				50–70 y
					Parallel	1 wk each		Placebo	0 mg	0
					2 treatments			Lycopene
16 mg	16
(125)	2012	Xaplanteris	19	M, F	Crossover	14 d	Tomato paste	No tomato	0 g	0		Lipid Px (↓)
				39 ± 13 y	2 treatments	Yes tomato		70 g	33.3
2-wk run-in/wash-out	Usual diet

¹AOX, antioxidant capacity; BC, baseline control; bw, body weight; CAT, catalase; CHD, coronary heart disease; Cu, Zn-SOD, superoxide dismutase with copper or zinc; F₂ Iso, F₂ isoprostane; FRAP, ferric-reducing antioxidant power; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GSSG, glutathione disulfide; HETE, hydroxyeicosatetraenoic acid; HNE, 4-hydroxynonenal or 4-hydroxy-2-nonenal; HW, healthy weight for height based on standard BMI criteria; MDA, malondialdehyde; NI, not indicated; OB, obese BMI; ORAC, oxygen radical absorbance capacity; OW, overweight BMI; Ox, oxidative; P, plasma; PCO, protein carbonyl content; PON-1, paraoxinase 1; Px, peroxide; QR/RR, glutamine/arginine; Se-GSH-Px, selenium cofactor for glutathione peroxidase; SOD, superoxide dismutase; Suppl, supplement; T2D, type 2 diabetes; TAC, total antioxidant capacity; TEAC, Trolox equivalent antioxidant capacity; tGSH, total glutathione; TJ, tomato juice; TRAP, total peroxyl radical trapping; U, Urine; 8-OH-dG, 8-hydroxydeoxyguanosine; ↓, decrease or reduction; ↑, increase; ―, neutral or no effect compared to control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

Collectively, there are stronger data supporting the consumption of tomato products to reduce oxidative stress and damage markers. Lycopene also appears to have a beneficial effect on oxidative damage but not as strong. Consuming tomato products consistently showed protection from lipid and DNA oxidative damage, as well as oxidation of LDLs; all of which present risks for CVD development and progression.

Inflammation: Tomatoes versus Lycopene

Over the past 2 decades substantial advances in basic and clinical science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis (57, 58, 94–97). Inflammation and oxidative stress are intimately linked. Changes in cellular redox status impact cellular processes, including NF-κB, a central signaling molecule in the induction of inflammation. NF-κB is a transcription factor that stimulates the encoding of a number of genes including those responsible for production of cytokines, chemokines, immunoreceptors, cell adhesion molecules, and acute phase proteins (98). Under conditions of oxidative stress, NF-κB is activated, resulting in an inflammatory response. Other important mediators of inflammation include pattern recognition receptors, such as toll-like receptors (TLRs), and kinases such as MAPK and c-Jun N-terminal kinase. The inflammatory response can be triggered by stimuli such as endotoxin (LPS from bacteria), viruses, and changes in amounts of ROS, FAs, cytokines, growth factors, and carcinogens.

Lycopene is a potent lipophilic antioxidant in vitro. Given the links between inflammation, oxidative stress, and obesity (a low-grade chronic inflammatory state) and chronic disease, investigations to determine the anti-inflammatory effects of lycopene or tomatoes have increased. Animal studies suggest a role for tomatoes and lycopene in reducing inflammation (99–102). C-reactive protein (CRP), an acute phase protein synthesized and secreted by the liver, is a commonly used marker of inflammation associated with CVD (103, 104). The CDC and the American Heart Association have established clinical cutoffs for CRP: low risk, <1 mg/L; intermediate risk, 1–3 mg/L; and high risk, >3 mg/L (104). Changes in select cytokines, chemokines, immunoreceptors, cell adhesion molecules, and/or acute phase proteins are also used to assess inflammation status in response to intervention (105, 106)

Changes in inflammatory status are an important component of determining CVD risk. Seven studies testing lycopene supplements reported changes in inflammatory biomarkers (Table 5). Of the 7 studies, 4 reported results for CRP: only 1 study reported a decrease in CRP (84), whereas the 3 others indicated no change in CRP (74, 107, 108). Changes in other inflammatory endpoints, such as IL-6, serum amyloid A (SAA), and TNF-α, were inconsistent (i.e., unchanged in some investigations and decreased in others) (see Table 5).

TABLE 5.

Clinical trials examining lycopene supplementation on markers of inflammation¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Lycopene source	Treatments	Lycopene dose	Inflammation findings
									mg/d
(73)	2004	Briviba	55	Smokers and nonsmokers	Parallel	2 wk	Lyc-O-Mato	Placebo	0	IL-4 (↓) (smokers)
				M	2 treatments			Lyc-O-Mato (taken after dinner)	14.6	TNF-α (—)
				32 ± 12 y	Double-blind					IL-2 (—)
			NK activity (—)
(85)	2006	Riso	26	M, F	Crossover	26 d	Lyc-O-Mato	Placebo	0	IFN-γ (—)
				HW	2 treatments			Lyc-O-Mato	5.7	TNF-α (↓)
26 ± 3 y	Double-blind
(107)	2008	Denniss	27	M, F (2:1)	Postprandial	1 wk	Lyc-O-Mato	Lycopene	80	CRP (—)
				HW, OW	1 treatment			Challenge meals
				18–26 y	BC			HFm: breakfast, 1107 kcal, 60 g fat
	LFm: breakfast, 1110 kcal, 243 g carbohydrate
(108)	2009	Markovits	16	OB, HW	1 treatment	4 wk	Lyc-O-Mato	Lycopene	30	CRP (—)
					BC					IL-6 (—)
	TNF-α (—)
(84)	2011	Kim	126	Healthy M	Parallel	8 wk each	Lycopene	Placebo	0	hsCRP (↓)
					3 treatments			Lycopene	6
	Lycopene	15
(74)	2012	Thies	225	M, F	Parallel	12 wk	Lycopene extract	Low tomato	0	CRP (—)
				HW, OW, OB	3 treatments	Low tomato + lycopene		10	IL-6 (—)
40–65 y	4-wk run-in	High tomato	32–50
(111)	2013	McEneny	54	M, F	Parallel	12 wk	Lycopene extract	Low tomato	0	SAA (↓) (serum)
				HW, OW, OB	3 treatments	Low tomato + lycopene		10	SAA (↓ (HDL)
40–65 y	4-wk run-in	High tomato	32–50

¹BC, baseline control; CRP, C-reactive protein; HFm, high-fat meal; hsCRP, high-sensitivity C-reactive protein; HW, healthy weight for height based on standard BMI criteria; LFm, low-fat meal; OB, obese BMI; OW, overweight BMI; SAA, serum amyloid A; ↓, decrease or reduction; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

Nine investigations examined the effect of tomato intake on changes in inflammatory biomarkers (Table 6). Of the 9 studies, 5 studies reported at least 1 marker [e.g., IL-6, TNF-α, CRP, monocyte chemoattractant protein 1 (MCP-1)] consistent with improved inflammation status (69, 78, 109–111). CRP was assessed in 5 studies. Although 1 study reported a decrease in CRP (78), 4 others measuring CRP reported no effect on CRP (65, 69, 74, 110). Heterogeneity across these studies in terms of sample size (up to n = 225), age of people studied, duration, and the dose and amount of tomato products consumed may account, at least in part, for the lack of consistency in results. Whether changes in other markers of inflammation are advantageous to overall health remains under intense investigation.

TABLE 6.

Clinical trials examining tomatoes and tomato products on markers of inflammation¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Tomato source	Treatments	Daily dose	Lycopene dose	Inflammation findings
										mg/d
(65)	2000	Upritchard	57	Diabetes (T2D)	Parallel	4 wk	Tomato juice	Placebo	500 mL (250 mL capsule ×2/d)	0	CRP (—)
				M, F	4 treatments	Tomato juice		44
				50s and 60s		4-wk placebo run-in
								Vitamin E	800 IU	0
Vitamin C	500 mg	0
(147)	2003	Watzl	22	Healthy M	Crossover	2 wk	Tomato juice	Carrot juice	300 mL	0	IL-2 (↑) with treatment, (—) b/n treatment
				2 treatments	Tomato juice	300 mL		37	IL-4 (—)
									HW	2-wk run-in, 2-wk washout, 2-wk run-out	TNF-α (↑) with treatment, (—) b/n treatment
									29 ± 6 y	Carotenoid depletion	NK cell cytotoxic (↑)
Lymphocyte proliferation (—)
(109)	2006	Sánchez-Moreno	12	Healthy M, F	1 treatment	14 d	Tomato soup	Tomato-based soup	500 mL, 250 mL ×2/d morning, evening	NI	IL-6 (—)
				BC	IL-1β (—)
					∼22 y						TNF-α (—)
											MCP-1 (↓)
PGE2 (↓)
(126)	2007	Blum	103 (1:1)	Healthy M, F	Parallel	1 mo	Tomato	No tomatoes	0 g	0	hsCRP (—)
				2 treatments	Yes tomatoes			300 g	30
				OW, OB	BC
46 ± 14 y	Usual diet
(78)	2008	Jacob	24	Healthy M,F	Parallel	2 wk	Tomato juice	Tomato juice	250 mL ×2/d	21	IL-1β (—)
				2 treatments	Tomato juice + vitamin C	250 mL ×2/d		21	TNF-α (↓)
						HW			2-wk run-in	CRP (↓)
19–27 y	AM, PM
(69)	2012	Burton-Freeman	25	Healthy M,F	Crossover	1 d	Tomato paste	Control meal	0 g	0	CRP (—)
				Postprandial	6 h	Tomato meal		94 g	27	IL-6 (↓)
				HW		2 treatments
(74)	2012	Thies	225	M, F (1:1.5)	Parallel	12 wk	Tomato products	Low tomato	Limited	0	CRP (—)
				HW, OW, OB	3 treatments	Low tomato + lycopene		10 mg	10	IL-6 (—)
40–65 y	4-wk run-in	High tomato	Points system	32–50
(110)	2013	Ghavipour	106	Healthy F	Parallel	20 d	Tomato juice	Water	110 mL ×3	0	IL-6 (↓) (OB only)
				2 treatments	Tomato juice			110 mL ×3	37	IL-8 (↓) (OW only)
				OW, OB							hsCRP (—)
20–40 y			with meals		TNF-α (↓) (OW only)
										mg/d
(111)	2013	McEneny	54	M, F	Parallel	12 wk	Tomato products	Low tomato	Limited	0	SAA serum (—)
				HW,OW,OB	3 treatments			Low tomato + lycopene	10 mg	10	SAA HDL (↓)
				40–65 y		4-wk run-in		High tomato	Points system	32–50

¹BC, baseline control; b/n, between; CRP, C-reactive protein; hsCRP, high-sensitivity C-reactive protein; HW, healthy weight for height based on standard BMI criteria; MCP-1, monocyte chemoattractant protein 1; NI, not indicated; OB, obese BMI; OW, overweight BMI; PGE2, prostaglandin F2a; SAA, serum amyloid A; T2D, type 2 diabetes; ↓, decrease or reduction; ↑, increase; –, neutral or no effect compared to control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

Overall, improvements in inflammatory markers such as CRP after lycopene supplementation were inconsistent. Studies using tomato products were also inconsistent in their findings for CRP, but tomato intake may provide some advantage showing improvements in other inflammatory markers (78, 109, 110) although their clinical utility remains undetermined. Collectively, the data are underwhelming for the anti-inflammatory effects of lycopene or tomato products; however, additional investigations are expected to yield new data on this topic.

Of note, on the basis of preclinical data and at least 1 trial, there are documented effects of tomato products on inflammation during the postprandial state (69). Future investigations may initially focus on understanding the shorter-term postprandial effect, and then move to longer duration trials thereafter. Addressing oxidative and inflammatory fluctuations and their derived insults during postprandial metabolism may be at the heart of innovation in effective food-based therapeutic strategies.

Endothelial Function: Tomatoes and Lycopene

The vascular endothelium is a critical regulator of vascular homeostasis. The endothelium has multiple functions as a semiselective barrier between the vessel lumen and surrounding tissues, regulating thrombosis and fibrinolysis, angiogenesis, and synthesis and secretion of vasodilating (e.g., NO) and vasoconstricting (e.g., endothelin-1) factors (34, 112, 113). Loss of proper endothelial function is a hallmark for vascular diseases and is often regarded as a key early event in the atherosclerotic process. A key mechanism of endothelial dysfunction is the lack of bioavailable NO (112). The prevailing wisdom for a lack of available endothelial-derived NO is an increase in ROS. Residual ROS, particularly O₂⁻ from exhausted defenses, reacts with NO to produce peroxynitrite (ONOO⁻), a harmful RNS in NO-producing endothelial cells (114, 115). Rapid degradation of NO by O₂⁻ is 1 of the most widely accepted mechanisms involved in the alteration of the eNOS/NO signaling pathway, resulting in impaired endothelial function.

Endothelial function is commonly assessed by FMD of the brachial artery. FMD is a noninvasive technique that assesses endothelium-dependent relaxation of the brachial artery as a surrogate marker of macrovascular endothelial function. Peripheral arterial tonometry is another relatively noninvasive technique that serves as a measure of peripheral microvascular endothelial function (116). Additional or alternative approaches for assessing endothelial function and responses to intervention include measures of platelet function and activation, leukocyte adhesion, and inflammatory and oxidative stress markers.

Cell culture experiments established that lycopene can protect NO from O₂⁻ destruction (117) and attenuate cytokine-induced endothelial cell adhesion molecule expression and leukocyte-endothelial interactions (118). Moreover, in mice, tomato supplementation protected against endothelial vasomotor dysfunction developed in response to a 4-mo atherogenic high-fat diet (119). Emerging evidence suggests a significant role of dietary factors in modulating endothelial function both negatively (120–122) and positively (123, 124). Western high-fat, high-carbohydrate diets increase markers of endothelial dysfunction, and consumption of certain plant components can reduce markers of dysfunction.

Few studies examined endothelial function in response to lycopene supplementation (Table 7; n = 3) or tomato consumption (Table 8; n = 6). Of the 3 trials testing lycopene supplements (74,84,107), only Kim et al. (84) reported a positive outcome among 126 individuals divided into 3 treatments (∼42/group) for 8 wk who consumed either 0, 6, or 15 mg lycopene/d. Effects were most apparent for 15 mg/d, which corresponded with improvements in microvascular function as measured by endo-peripheral arterial tonometry as well as decreased concentrations of soluble intracellular adhesion molecule (sICAM) and soluble vascular adhesion molecule (sVCAM). A concomitant decrease in systolic BP was also observed, along with improvements in inflammatory and oxidative stress status.

TABLE 7.

Clinical trials examining lycopene supplementation on markers of endothelial function¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Lycopene source	Treatments	Lycopene dose	FMD findings
									mg/d
(107)	2008	Denniss	27	M, F (2:1)	Postprandial	1 wk	Lyc-O-Mato	Lycopene	80	sICAM (—), sVCAM (—)
				HW, OW	1 treatment
				18–26 y	BC			Challenge meals
								HFm: breakfast, 1107 kcal, 60 g fat
								LFm: breakfast,  1110 kcal, 243 g carbohydrate
(84)	2011	Kim	126	Healthy M	Parallel	8 wk each	Lycopene	Placebo	0	ENDO-PAT (↑)
				3 treatments	Lycopene			6	sVCAM (↓)
		Lycopene	15	sICAM (↓)
(74)	2012	Thies	225	M, F	Parallel	12 wk	Lycopene extract	Low tomato	0	ICAM-1 (—)
				HW, OW, OB	3 treatments	4-wk run-in		Low tomato + lycopene	10
40–65 y			High tomato	32–50

¹BC, baseline control; ENDO-PAT, endo-peripheral arterial tonometry; FMD, flow-mediated dilation; HFm, high-fat meal; HW, healthy weight for height based on standard BMI criteria; ICAM-1, intracellular adhesion molecule 1; LFm, low-fat meal; OB, obese BMI; OW, overweight BMI; sICAM, soluble intracellular adhesion molecule; sVCAM, soluble vascular cellular adhesion molecule; ↓, decrease or reduction; ↑, increase; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

TABLE 8.

Clinical trials examining tomato and tomato products on markers of endothelial function¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Tomato source	Treatments	Daily dose	Lycopene dose	FMD findings
										mg/d
(65)	2000	Upritchard	57	Diabetes (T2D)	Parallel	4 wk	Tomato juice	Placebo	0 mL	0	ICAM-1 (—)
				M, F	4 treatments	4-wk placebo run-in		Tomato juice	500 mL (250 mL ×2)	44	VCAM-1 (—)
				50–60 y
								Vitamin E	800 IU	0
			Vitamin C	500 mg	0
(126)	2007	Blum	103	Healthy M, F	Parallel	1 mo	Tomato	No tomatoes	0 g	0	sICAM (↑) (P = 0.07)
				2 treatments	Yes tomatoes			300 g	30
				OW, OB	BC						sVCAM (—)
46 ± 14 y		Usual diet			E-selectin (—)
(148)	2011	Stangl	19	Postmenopausal F	Crossover	24 h	Tomato purée	No tomato purée	0 g		FMD (—)
					2 treatments	7 d		Tomato purée with buttered roll	70 g
(69)	2012	Burton-Freeman	25	Healthy M,F	Crossover	1 d	Tomato paste	Control meal	0 g	0	FMD (—)
				Postprandial	6 h	Tomato meal		94 g	27
HW	2 treatments
(74)	2012	Thies	225	M, F (1:1.5)	Parallel	12 wk	Tomato products	Low tomato	Limited	0	ICAM-1 (—)
				HW, OW, OB	3 treatments	4-wk run-in		Low tomato + lycopene	10-mg capsule	10	PWV (—) (arterial stiffness)
40–65 y			High tomato	Points system	32–50
(125)	2012	Xaplanteris	19	M, F	Crossover	14 d	Tomato paste	No tomato	0 g	0	FMD (↑)
				39 ± 13 y	2 treatments	2-wk run-in/ wash-out		Yes tomato	70 g	33.3
		Usual diet

¹BC, baseline control; FMD, flow-mediated dilation; HW, healthy weight for height based on standard BMI criteria; ICAM-1, intracellular adhesion molecule 1; OB, obese BMI; OW, overweight BMI; PWV, pulse wave velocity; sICAM, soluble intracellular adhesion molecule; sVCAM, soluble vascular cellular adhesion molecule; T2D, type 2 diabetes; ↑, increase; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

For tomato intake, only 1 of 6 studies reported a positive increase in endothelial function as measured by FMD (∼3.3% increase) (125). The increase in FMD was shown after a 2-wk washout (baseline) followed by 14 d of inclusion of 70 g tomato paste added into participants’ usual diet versus no added tomato paste to the diet.

Adhesion molecules are another indicator of endothelial disruption, although they are also considered markers of inflammation that are associated with the vascular endothelium. A marginally significant (P = 0.07) improvement in adhesion molecules (sICAMs) was observed after 1 mo of adding tomatoes (compared with no tomatoes) to the diet (126); however, other markers (sVCAM and E-selectin) were unchanged. Overall, few investigations have addressed the effects of lycopene or tomato intake on endothelial function.

BP: Tomatoes and Lycopene

Normal BP is continuously regulated by the autonomic nervous system through an extensive network of receptors, hormones, and nerves. The endothelium is critical in the maintenance of normal BP. Likewise, endothelial dysfunction is recognized for its role in hypertension and vascular disease. Central to the function of the endothelium is sufficient NO bioavailability, a master molecule known for its important relaxant properties and influence on BP (127, 128). Oxidative stress conditions decrease the bioavailability of NO. Therefore, consuming antioxidants has potentially beneficial effects on BP control and CVD risk.

To date, 5 lycopene supplement and 3 tomato studies (Tables 9 and 10, respectively) have tested their effects on BP. In 3 of 5 lycopene supplement studies, lycopene at 15 mg/d for 6–8 wk decreased systolic BP (60, 84, 129) and decreased diastolic BP (60, 129). The benefits were apparent in individuals with stage 1 hypertension (60, 129) who were otherwise healthy (84). Two other studies reported no differences in BP after lycopene supplementation at similar doses and duration (74, 130).

TABLE 9.

Clinical trials examining lycopene supplementation on blood pressure¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Lycopene source	Treatments	Lycopene dose	Blood pressure findings
									mg/d
(60)	2006	Engelhard	31	Grade 1 hypertension	Sequential, 2 treatments	16 wk: 4 wk placebo, 8 wk treatment, 4 wk placebo	Lyc-O-Mato	Placebo	15	SBP (↓)
				30–70 y				Lyc-O-Mato with meals		DBP (↓)
				No medications
(129)	2009	Paran	50	Grade 1 hypertension	Crossover	6 wk each	Lyc-O-Mato	Placebo	15	SBP (↓)
					2 treatments			Lyc-O-Mato with meals		DBP (↓)
					Double-blind				1–2 medications
								ACE (10 mg)
				CCB (5 mg)
46–66 y	β Blockers (25 mg)
(130)	2009	Ried	36	Prehypertension	Parallel -1	8 wk each	Lyc-O-Mato	Placebo	15	SBP (—)
				HW, OW	Crossover -2/ active treatment only			Tomato extract		DBP (—)
50 ± 12 y	3 treatments	Dark chocolate
(84)	2011	Kim	126	Healthy M	Parallel	8 wk each	Lycopene	Placebo	0	SBP (↓)
					3 treatments			Lycopene	6
Lycopene	15
(74)	2012	Thies	225	M,F (1:1.5)	Parallel	12 wk	Lycopene extract	Low tomato	0	SBP (—)
				HW, OW, OB	3 treatments			Low tomato + lycopene	10	DBP (—)
40–65 y	4-wk run-in	High tomato	32–50

¹ACE, angiotensin converting enzyme; CCB, calcium channel blocker; DBP, diastolic blood pressure; HW, healthy weight for height based on standard BMI criteria; OB, obese BMI; OW, overweight BMI; SBP, systolic blood pressure; ↓, decrease or reduction; —, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

TABLE 10.

Clinical trials examining tomato and tomato products on blood pressure¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Tomato source	Treatments	Daily dose	Lycopene dose	Effects on blood pressure
										mg/d
(65)	2000	Upritchard	57	Diabetes (T2D)	Parallel	4 wk	Tomato juice	Placebo	Capsule, 500 mL (250 mL ×2)	0	SBP (—)
				M, F	4 treatments			Tomato juice		44	DBP (—)
				<75 y		4-wk placebo run-in		Vitamin E	0
				50s and 60s				Vitamin C	800 IU	0
500 mg
(131)	2011	Shidfar	32	Diabetes (T2D)	1 treatment	8 wk	Tomato, raw	Raw tomato	200 g		SBP (↓)
				M	BC	2-wk non-tomato run-in			At lunch	DBP (↓)
				HW, OW
40–60 y
(74)	2012	Thies	225	M, F	Parallel	12 wk	Tomato products	Low tomato	Limited	0	SBP (—)
				HW, OW, OB	3 treatments			Low tomato + lycopene	10 mg	10	DBP (—)
40–65 y	4-wk run-in	High tomato	Points system	32–50

¹BC, baseline control; DBP, diastolic blood pressure; HW, healthy weight for height based on standard BMI criteria; OB, obese BMI; OW, overweight BMI; SBP, systolic blood pressure; T2D, type 2 diabetes; ↓, decrease or reduction; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

Among 3 studies, tomato products decreased BP in individuals with type 2 diabetes after 8 wk of consumption of 200 g raw tomatoes (131); however, no changes were observed in a second investigation in individuals with type 2 diabetes or in those who were relatively healthy after consumption of 500 mL tomato juice or a high-tomato diet for 4 or 12 wk, respectively (65, 74). It is not clear whether tomato type, intervention duration, sample size, amount consumed, or starting BP influenced the results. Overall, the data for tomato products suggest that a higher initial BP results in more favorable declines in BP (60, 129, 132), such that those with prehypertension or hypertension may be better indicated for improvements in BP.

In summary, there is promising evidence for a role for both lycopene supplementation and tomato products for improvements in systolic and diastolic BP. To date, data are more supportive for lycopene supplementation than tomato intake for reducing BP. Additional research is needed to determine the mechanisms through which lycopene and tomato intake affects BP control. Tomatoes provide several other essential nutrients and phytochemicals that support healthy BP, including potassium and fiber.

Lipids: Tomatoes and Lycopene

Elevated TC, elevated LDL cholesterol, and lower HDL cholesterol are widely recognized as risk factors for CVD. The relation between lycopene and tomato product ingestion and cholesterol metabolism was recently reviewed (56). Briefly, possible mechanisms implicated in cholesterol reduction by lycopene and tomato derivatives include decreased cholesterol synthesis through inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and expression, modulation of LDL receptors, and inhibition of acetyl-coA acetyltransferase activity (56). Although animal and cell culture studies have revealed favorable effects of lycopene and tomato feeding on lipid and cholesterol metabolism, the literature is inconsistent. Of 11 clinical trials testing the effects of lycopene supplementation (Table 11), only 1 showed improvements in TC, LDL cholesterol, and HDL cholesterol, although an increase in TGs was also reported in these postmenopausal women (80). Another study reported improvements in TGs but not in TC, LDL cholesterol, or HDL cholesterol when combined with fish oil (62). One study measured LDL particle size, finding increased size after lycopene supplementation (84), which is favorable for CVD risk reduction on the basis of findings that smaller, dense LDLs are more atherogenic (57, 58). In contrast, among 14 clinical trials that provided tomato products for 1 to 12 wk (Table 12), TC decreased in only 3 studies (70, 71, 78), LDLs decreased in 2 studies (71, 79), HDLs increased in 3 studies (79, 133, 134), and apoA-1, involved with HDL metabolism, was increased in 1 other study (131). Improvements in TGs were reported in 1 study (79).

TABLE 11.

Clinical trials examining lycopene supplementation on lipids¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Lycopene source	Treatments	Lycopene dose	Lipid findings
									mg/d
(59)	1998	Agarwal	19	M, F	Crossover	1 wk each	Lyc-O-Mato	Placebo	0	TC (—)
				OW	4 treatments			Lyc-O-Mato	75	TG (—)
				25–40 y				Spaghetti sauce	39.2	LDL (—)
		Tomato juice	50.4	HDL (—)
(143)	1999	Böhm	22	F	Parallel	6 wk	Lyc-O-Mato	Lyc-O-Mato	5	TC (—)
				HW	3 treatments			Tomato	5	TG (—)
				20–27 y				Tomato juice with dinner	5	HDL (—)
(62)	2003	Kiokias	32	M, F	Crossover	3 wk each	Lyc-O-Mato	Fish oil	0	TC (—)
				HW	2 treatments			Fish oil + carotenoid extract with Lyc-O-Mato	4.5	TG (↓)
				32 ± 11 y	Double-blind				LDL (—)
				HDL (—)
(60)	2006	Engelhard	31	Grade1 hypertension	Sequential	16 wk: 4 wk placebo, 8 wk treatment, 4 wk placebo	Lyc-O-Mato	Placebo		TC (—)
				30–70 y	2 treatments			Lyc-O-Mato with meals	15	TG (—)
				No medications						LDL (—)
								HDL (—)
										apoA-1 (—)
				apoB (—)
(80)	2006	Misra	41	Healthy postmenopausal F	Parallel	6 mo	LycoRed	HRT	0	TC (↓)
					2 treatments			LycoRed	4	TG (↑)
									LDL (↓)
				HW, OW						HDL (↑)
46 y
(79)	2007	Shen	24	Volunteers, Undefined	Parallel	6 wk	Lycopene, food-grade	Lycopene	∼40	TC (—)
				HW	3 treatments			Tomatoes, small raw		TG (—)
				18–23 y	BC			Tomato juice		LDL (—)
								Lunch and dinner		HDL (—)
			VLDL (—)
(107)	2008	Denniss	27	M, F (2:1)	Postprandial	1 wk	Lyc-O-Mato	Lycopene	80	TC (—)
				HW, OW	1 treatment					TG (—)
				18–26 y	BC			Challenge meals		HDL (—)
								HFm: breakfast, 1107 kcal, 60 g fat
		LFm: breakfast, 1110 kcal, 243 g carbohydrate
(63)	2008	Devaraj	77	M, F	Parallel	8 wk	Lycopene, beadlet, all trans	Placebo	0	TC (—)
				OW	4 treatments			Lycopene	6.5	TG (—)
				>40 y	Double-blind			Dose-response	15	LDL (—)
			30	HDL (—)
(136)	2010	Talvas	30	Healthy M	Parallel	1 wk each	Lycopene	Placebo	0	TC (—)
				2 treatments		Lycopene		16	TG (—)
				OW	Crossover
				50–70 y	2 treatments	1 wk each		Yellow tomato paste	0
			Red tomato paste	16
									mg/d
(84)	2011	Kim	126	Healthy M	Parallel	8 wk each	Lycopene	Placebo	0	LDL size (↑)
				3 treatments	Lycopene			6
		Lycopene	15
(74)	2012	Thies	225	M, F	Parallel	12 wk	Lycopene	Low tomato	0	TC (—)
				HW, OW, OB	3 treatments	4-wk run-in		Low tomato + lycopene	10	TG (—)
				40–65 y				High tomato	32–50	LDL (—)
										HDL (—)
										apoA-1 (—)
					apoB-100 (—)

¹BC, baseline control; HFm, high-fat meal; HRT, hormone replacement therapy; HW, healthy weight for height based on standard BMI criteria; LFm, low-fat meal; OB, obese BMI; OW, overweight BMI; TC, total cholesterol;↓, decrease or reduction; ↑, increase; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

TABLE 12.

Clinical trials examining tomato and tomato products on lipids¹

Reference	Year	First author	n	Participant characteristics	Study design	Length of treatment	Tomato source	Treatments	Lycopene dose	Lipids
(59)	1998	Agarwal	19	Healthy M, F	Crossover	1 wk each	Tomato juice	Placebo	0 mg	TC (—)
				4 treatments	Spaghetti sauce		Lyc-O-Mato	75 mg	TG (—)
				OW				Spaghetti sauce	39.2 mg	LDL (—)
25–40 y			Tomato juice	50.4 mg	HDL (—)
(65)	2000	Upritchard	57	Diabetes (T2D)	Parallel	4 wk	Tomato juice	Placebo	0 mg	TC (—)
				M,F	4 treatments	4-wk placebo run-in		Tomato juice	44 mg
				<75 y				Vitamin E	0 mg
50s and 60s				Vitamin C	0 mg
(70)	2003	Hadley	60	Healthy M, F	Parallel	15 d	Tomato soup	Tomato soup (condensed)	35 mg	TC (↓)
				3 treatments		V8 juice			TG (—)
				>40 y	BC	1-wk run-in (lycopene free)		Tomato soup (RTE)	23 mg
				V8 juice	25 mg
(135)	2004	Collins	10	Healthy M, F	Crossover	3 wk each	Tomato juice	No tomatoes	0 mg	TC (—)
				3 treatments	2-wk run-in, 4-wk washout		Tomato juice	18.4 mg	TG (—)
				HW, OW, OB				Watermelon juice	20.1 mg	HDL (—)
35–68 y
(133)	2006	Blum	98	Healthy M, F	Parallel	1 mo	Tomato	No tomatoes	0 mg	TC (—)
				2 treatments	Yes tomatoes			30 mg	TG (—)
				OW, OB	BC					HDL (↑)
				46 ± 14 y				Usual diet		LDL (—)
				VLDL (—)
(92)	2006	Bose	90	Healthy and diabetes (T2D)	1 treatment	60 d	Tomatoes (cooked)	Tomatoes (cooked)	200 g in Suppl group (n = 30)	TC (—)
				n = 50, healthy	BC	(n = 30 of T2D only)				TG (—)
				n = 40, T2D						HDL (—)
				n = 30, Suppl						LDL (—)
		VLDL (—)
(134)	2006	Madrid	17	Healthy M, F	1 treatment	7 d	Tomato juice	Tomato juice	∼18 mg/70 kg	TC/HDL (↓)
BC	HDL ↑
(93)	2007	Bose	80	Healthy and CHD	1 treatment	60 d	Tomato (cooked)	Tomatoes (cooked)	∼25 g	TC (—)
				n = 50, healthy	BC					TG (—)
				n = 30, CHD						HDL (—)
				n = 20 CHD Suppl						LDL (—)
	VLDL (—)
(79)	2007	Shen	24	Unspecified	Parallel	6 wk	Tomato juice	Small raw tomatoes	∼40 mg	TC (—)
				HW	3 treatments		Tomato, raw	Tomato juice		TG (↓) (TJ, T)
				18–23 y	BC			Food-grade lycopene		LDL (↓) (TJ)
								Lunch and dinner		HDL (↑) (TJ, T)
				VLDL (—)
(71)	2007	Silaste	21	Healthy M ,F	Sequential	3 wk	Tomato juice	Low tomato diet	27 mg	TC (↓)
				2 treatments	2-wk baseline, 3-wk low-tomato diet	Ketchup	High tomato diet	TG (—)
				HW	BC			Eat with all main meals		HDL (—)
20–49 y					LDL (↓)
(78)	2008	Jacob	24	Healthy M,F	Parallel	2 wk	Tomato juice	Tomato juice	21 mg	TC (↓)
				2 treatments	2-wk run-in		Tomato juice + vitamin C	21 mg	TG (—)
				HW
19–27 y
(136)	2010	Talvas	30	Healthy	Crossover	1 wk each	Tomato paste	Yellow tomato	0 mg	TC (—)
				OW	2 treatments			Red tomato	16 mg	TG (—)
				50–70 y
					Parallel	1 wk each		Placebo	0 mg
	2 treatments			Lycopene	16 mg
(131)	2011	Shidfar	32	Diabetes (T2D)	1 treatment	8 wk	Tomato, raw	Raw tomato		apoB (—)
				M	BC				apoA-1 (↑)
40–60 y		2-wk non-tomato run-in
(74)	2012	Thies	225	M, F	Parallel	12 wk	Tomato products	Low tomato	0 mg	TC (—)
				HW, OW, OB	3 treatments	4-wk run-in		Low tomato + lycopene	10 mg	TG (—)
				40–65 y				High tomato	32–50 mg	LDL (—)
										HDL (—)
										apoA-1 (—)
					apoB-100 (—)

¹BC, baseline control; HW, healthy weight for height based on standard BMI criteria; OB, obese BMI; OW, overweight BMI; Suppl, supplement; T, tomato T2D, type 2 diabetes; TJ, tomato juice; RTE, ready to eat; TC, total cholesterol; ↓, decrease or reduction; ↑, increase; ―, neutral or no effect compared with control arm, P < 0.05 (or baseline in 1-arm trials, P < 0.05).

A major drawback of the tomato-based clinical trials is that few compared effects against a control diet, and therefore relied on examining changes from baseline. Comparator group differences have tended to be stronger. Among the investigations reporting no effect of tomato products on lipid endpoints, 5 investigations had a comparison group (59, 65, 74, 135, 136). These data emphasize the importance of having proper controls to better understand the efficacy of specific interventions.

One research area that deserves more attention is the role of tomato and lycopene intake on HDL metabolism. Three tomato-based studies (79, 133, 134) and 1 lycopene supplement study (80) revealed improvements in HDL cholesterol. HDLs must be functional to be protective (137); apoA-1 is a critical component of HDLs and when its production is lacking or displaced from HDLs, HDLs are rendered relatively dysfunctional. In states of chronic low-grade inflammation, such as obesity, apoA-1 can be displaced by the inflammatory protein SAA; the adipose tissue is a major source of SAA. HDLs rendered dysfunctional by this exchange promote a proatherogenic phenotype and increase cholesterol ester (CE) deposition in the arterial wall by enhancing CE uptake by macrophages and reducing reverse CE transport. The modified HDLs act much like modified/oxidized LDLs to promote an overall unstable vessel environment. Modified HDLs are also less effective in protecting LDLs from oxidation via HDL–paraoxonase-1 (PON-1) activity and presence (137), adding to the inflamed vessel environment. Therefore, dietary strategies that can increase HDL cholesterol and or at minimum preserve the functionality of HDLs would have important therapeutic and disease risk–lowering implications.

In a recent investigation by McEneny et al. (111), 54 moderately overweight, middle-aged individuals consumed <10 mg/wk of lycopene (control), 224–350 mg/wk dietary lycopene from tomato-based products, or 70 mg/wk lycopene supplement for 12 wk. The associations with SAA and HDL fractions were evaluated along with other functional indicators such as PON-1 activity. Serum and HDL fractions were enriched with lycopene compared with control after the food-based and supplement intervention. SAA was reduced in the HDL₃ fraction and PON-1 activity increased after lycopene supplementation. The dietary/tomato lycopene intervention produced intermediate results. Overall, supportive evidence continues to accumulate for a role of lycopene in HDL metabolism and functionality.

Summary and Conclusions

The purpose of this review was to examine the available human clinical trials assessing the efficacy of lycopene supplements versus tomato products on CVD risk factors. Epidemiologic investigations describing an inverse relation between blood and tissue lycopene concentrations and risk of CVD along with preclinical data revealing biologic activity of lycopene support the hypothesis that lycopene and/or tomatoes may be associated with reductions in CVD risk. A major question, however, is whether lycopene as a dietary supplement can deliver cardiovascular benefits equivalent to tomatoes. History indicates that single-nutrient approaches often fail and on occasion are harmful (138). Nonetheless, there continues to be interest by consumers and a booming dietary supplement industry built on sales of naturally and synthetically derived individual nutrients and dietary components, of which lycopene and tomatoes are 1 example.

We have reviewed the results of lycopene supplementation and tomato-based food interventions on traditional and emerging CVD risk factors. Our goal was to determine whether there was compelling evidence in favor of lycopene supplementation or tomato intake to reduce CVD risk. We focused on oxidative stress and damage, inflammation, endothelial function, BP, and lipid metabolism for this review. Lycopene is a well-established phytochemical with numerous clinical trials published to date.

Overall, there was more support for consuming tomato products versus taking a lycopene supplement daily for improvements in lipoproteins (e.g., LDL oxidation), lipids, and protein and DNA from oxidative damage. Results were underwhelming for both tomato products and lycopene supplements on selected inflammatory markers such as CRP. However, the available evidence remains limited and represents an opportunity for future research on the anti-inflammatory activity of tomatoes and lycopene. Specifically, the study of tomato and lycopene activity on acute disturbances, such as metabolic inflammation during postprandial metabolism, may provide insight for designing efficacy trials assessing long-term benefits.

Lycopene supplementation was shown in 3 of 5 studies to reduce BP, whereas tomato intake reduced BP in 1 of 3 clinical trials. The evidence favors lycopene supplementation as a therapeutic strategy in lowering BP among hypertensive individuals (60, 129). However, Kim et al. (84) reported reduced systolic BP at a similar dose (15 mg/d lycopene) in healthy participants, suggesting that lycopene may also have a role in reducing or maintaining BP within the normal range.

Finally, improvements in lipid metabolism are modest but supportive for tomato intake versus taking a lycopene supplement. The emerging focus on HDL metabolism and function for tomato intake is a promising area of research. Likewise, although only 1 study examined LDL particle size to date (84), this represents another potential research opportunity for lycopene and tomatoes.

Tomatoes provide a number of key nutrients and phytochemicals, including lycopene, that support cardiovascular health. The study of bioactive components in foods and/or supplements is growing, in part due to consumer interest and new market opportunities. Tomatoes and lycopene are good examples of intensified attention by consumers, researchers, and industry. Considering the diverse interests, some of which may be overlapping (intellectual, health, economical), research is of paramount importance to support appropriate messaging, claims, and recommendations about tomatoes and lycopene intake. The present review highlights the need for more targeted research; however, at present, the available trials support consuming tomato-based foods as a first-line approach compared with lycopene supplementation, with the exception of BP management. Future research that is well designed, clinically focused, mechanistically revealing, and relevant to human intake will undoubtedly add to the growing body of knowledge unveiling the promise of tomatoes and/or lycopene supplementation as an integral component of a heart-healthy diet.