Review Article

Narges Hedayati1
Protective effect of lycopene against Mehri Bemani Naeini2
chemical and natural toxins: A review Alireza Nezami1
Hossein Hosseinzadeh1,3
A. Wallace Hayes4,5
Sarasadat Hosseini1
Mohsen Imenshahidi1,3
Gholamreza Karimi 1,3*
1
Department of Pharmacodynamics and Toxicology, School of
Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
2
Nanotechnology Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical Sciences, Mashhad, Iran
3
Pharmaceutical Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical Sciences, Mashhad, Iran
4
University of South Florida College of Public Health, Tampa, FL, USA
5
Michigan State University Institute for Integrative Toxicology, East
Lansing, MI, USA

Abstract
People are exposed to a number of environmental, occupa-
tional, and therapeutic toxic agents which may be natural or
man made. These hazardous substances may manifest as
direct side effects on the function of organs or indirectly
induced alteration of gene expression, cancer-associated meta-
bolic pathways, and/or alter homeostasis. Lycopene, as a one
of the most potent antioxidant, is found in fruits and vegeta-
bles. High-intake of lycopene has been shown to be effective in
decreasing the risk of both natural toxins including mycotoxins,
bacterial toxins, and chemical toxins including heavy metals,
pesticides as well as herbicides. Recently, there is growing
attention in understanding the mechanisms of the phytochemi-
cals and carotenoids as antioxidative, antiapoptotic, radical
scavenging, and chelating agents and their roles in the modula-
tion of inflammatory pathways. This review summarizes avail-
able data from several recent studies about lycopene and its
role against chemical and natural toxicants. © 2018 BioFactors,
00(00):1–19, 2018

Keywords: lycopene; antioxidants; carotenoid; mycotoxins; heavy

metals

Abbreviations: AFB, Aflatoxin B1; AFM, Aflatoxin M1; AFP1, Aflatoxin P1; AFQ1, Aflatoxin Q1ALT: alanine aminotransferase; ALAD, δ-Aminolevulinate
dehydratase; ALI, Acute lung injury; ALP, Alkaline phosphatase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AST, Aspartate amino trans-
ferase; Aβ, Amyloid beta; BUN, Blood urea nitrogen; CAT, Catalase; CGNs, Cultured cerebellar granule neurons; COX-2, Cyclooxygenase 2; CPK, Creatine
phosphokinase; CRP, C-reactive protein; cTnT, Cardiac troponinT; D-GalN/LPS, D-galactosamine/lipopolysaccharide; ERK1/2, Extracellular signal-regulated
kinase; GPx1, Glutathione peroxidase 1; GSH, Glutathione; GSH/GSSG, Glutathione to oxidized glutathione ratio; GST, Glutathione S-transferase; Hb, Hemo-
globin; HDL, High density lipoprotein; HSP-70, Heat-shock protein 70; Ht, Hematocrit; IGF-1, Insulin-like growth factor 1; IkBα, inhibitor of kappa B alpha; IL-
1β, Interleukin 1 beta; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; LDH, Lactate dehydrogenase; LDL, Low density lipoprotein; LPO, Lipid perox-
idation; LPS, Lipopolysaccharide; LPS/GaIN, Lipopolysaccharide/D-galactosamine; Lyc, Lycopene; MAPK, Mitogen-activated protein kinase; MC-LR, Micro-
cystin-LR; MN, Micronucleus assay; MPO, Myeloperoxidase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA, N-methyl-D-
aspartate; NO, Nitric oxide; Nrf2, Nuclear factor erythroid 2-related factor 2; OTA, Ochratoxin A; PA, Phagocytic activities; PARP, Poly (ADP-ribose) polymer-
ase; RBC, Red blood cell; ROS, Reactive oxygen species; SNc, Substantia Nigra Pars Compacta; SOD, Superoxide dismutase; T3, Triidothyronine; TAC,
Total antioxidant capacity; TBA, Total bile acids; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCHO, Total cholesterol; TGF-β, Transforming growth factor beta 1;
TI, Total immunoglobulin levels; TLE, Tomato lycopene extract; TNF-α, Tumor necrosis factor alpha; TP, Total plasma protein; TRAF6-NF-kB, Tumor necrosis factor
receptor-associated factor 6; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling; Vit A, Vitamine A; WBC, White blood cell; γ-GT, Gamma glutamyl
transferase
© 2018 International Union of Biochemistry and Molecular Biology
Volume 00, Number 00, Month 2018, Pages 1–19
*Address for correspondence: Gholamreza Karimi, PhD, Pharmaceutical Research Center and School of Pharmacy, Mashhad University of Medical Sciences,
Mashhad, P.O. Box, 1365-91775, Iran. Tel.: +98 511 882 3255; Fax: +98 511 882 3251; E-mail: karimig@mums.ac.ir
Received 13 June 2018; accepted 6 September 2018
DOI 10.1002/biof.1458
Published online 00 Month 2018 in Wiley Online Library
(wileyonlinelibrary.com)

BioFactors 1

1. Introduction
Lycopene, a red carotene and carotenoid pigment, is phyto-
chemical compound found in tomatoes, watermelons, apricots,
and other red fruits and vegetables. Compositions that are not
red may also comprise lycopene, such as asparagus and pars-
ley. Although lycopene is chemically a carotene, it has no vita-
min A activity. It is a noncyclic carotenoid which has a
molecular weight of 536.85 Daltons and is insoluble in water.
Dietary antioxidants, such as lycopene, play a role in prevention
of lipid, protein, and DNA oxidation and related diseases. While
lycopene is a stable molecule, it can undergo oxidative, thermal
and photo-degradation [1]. The in vitro antioxidant potency of
lycopene, up to 100 times more efficient than vitamin E, its che-
mopreventive activity [2] against certain types of cancers, and
its protective activity against chemotherapeutic-induced renal
damage have attracted considerable research activity in recent
years [3]. Lycopene has been widely used in traditional medi-
cine and has been reported to have protective effects on treat-
ment of cardiovascular diseases [4], neurotoxicity [5], hepatic
injury [6], nephrotoxicity [7], as an antioxidant [8], and as an
antiapoptotic agent [9]. The protective role of lycopene on toxi-
cant induced toxicity is discussed in this review.
2. Natural toxins
Lycopene has been reported to exhibit protective effects against
several toxins, including some mycotoxins and bacterial toxins.
2.1. Mycotoxins
Aflatoxin
The aflatoxins, significant food contaminants, are produced by
Aspergillus flavus and Aspergillus parasiticus. Aflatoxin B1
(AFB1) is a genotoxic hepatocarcinogen [10]. The phase
1 metabolism of AFB1 was significantly reduced in male and
female F344 rats pretreated with lycopene (100 mg/kg, orally
for 3 weeks) as demonstrated by a decreased in the metabo-
lites, AFP1, AFQ1, and AFM1, in urine suggesting that lycopene
may selectively inhibits certain phase 1 cytochrome p45s such
as Cyt 3A4, Cyt 2A6, and Cyt 1A2. Serum levels of
AFB1-albumin adduct, levels of AFB-N7-Gua adduct in hepatic
DNA and the levels of AFB-N7-Gua excreted in the urine were
also significantly reduced. Excretion of AFB1-mercapturic acid,
the phase 2 detoxification metabolite of AFB1, was significantly
increased in lycopene-treated animals [11]. In another study,
AFB1 (2.5 mg/kg, single dose, i.p) significantly decreased sperm
motility, seminifer epithelium thickness and increased the num-
ber of abnormal sperms. The level of malondialdehyde in the
testicular tissue was higher in AFB1 treated rats than in control
animals. Supplementation with lycopene (10 mg/kg, orally)
reduced testicular damage and the oxidative stress induced by
AFB1 [12]. In addition, lycopene (10 mg/kg, orally) combined
with vitamin E (10 mg/kg/day, orally) for 12 days had a protec-
tive effect against AFB1 (2.5 mg/kg on the 12th day) induced
damage to the gastric mucosa in rats. The combination
2 lycopene against chemical and natural toxins
BioFactors
increased the level and function of sulphomucins (mucins with
sulphate groups) while decreasing the levels of mucus and
phospholipid, which are essential in the gastric mucosal bar-
rier [13].
Totally, these results suggest that inhibition of metabolic
activation and induction of detoxification enzymes are the main
mechanisms for the protective effects of lycopene against afla-
toxin toxicity [11].
Ochratoxin A
The ochratoxins are secondary metabolites of Aspergillus and
Penicillium species [14]. Ochratoxin A (OTA) is a nephrotoxin, a
reproductive toxicant and a possible hepatotoxin. The protec-
tive effects of lycopene against OTA (0.5 mg/kg, 14 days orally)
induced DNA damage has been reported. Lycopene (5 mg/kg for
given orally both 7 and 14 days) provided a significant decrease
of comet tail in the kidney and liver cells versus OTA only trea-
ted rats [15]. In addition, the partially protective effect of lyco-
pene against OTA (0.5 mg/kg/day, orally for 14 days) induced
renal apoptosis and toxicity has been suggested in male
Sprague-Dawley rats. Lycopene treatment (5 mg/kg/day, orally
for 14 days) increased glutathione (GSH) levels and induced
renal glutathione peroxidase 1 (GPx1) activity [16]. Palabiyik
et al. [16] also reported that lycopene (5 mg/kg/day by gavage
for 14 days) reduced the OTA induced renal oxidative stress
and apoptosis in rats based on data obtained from their termi-
nal deoxynucleotidyl transferase dUTP nick end labeling analy-
sis which showed a decrease in apoptotic cell death.
2.2. Bacterial toxins
Lipopolysaccharide
Bacterial lipopolysaccharide (LPS), a glycolipid structure on the
outer membrane of gram-negative bacteria, elicits a strong
immune response in animals [17]. LPSs are responsible for
inflammatory reactions (Table 1) [18]. Lycopene (5–20 μM) sig-
nificantly suppressed the production of LPS (100 ng/ml) induced
proinflammatory cytokines such as interleukin 1 beta (IL-1β),
tumor necrosis factor alpha (TNF-α), and nitric oxide (NO) in
rat primary cultured microglia. These results indicated that
inhibition of the activity of microglia by lycopene may be associ-
ated with inactivation of extracellular signal-regulated kinase
(ERK1/2) [18]. In addition, tomato lycopene extract (TLE)
(100 μg/mL) inhibited LPS (5 μg/mL) induced gene expression in
murine splenocytes through prevention of nuclear factor
kappa-light-chain-enhancer of the activated B cells (NF-κB)-
signaling pathway which in turn enhanced apoptosis in IEC-18
cells, which is mediated by obstruction of IkBα degradation,
RelA nuclear translocation and transcription activity [19]. Lyco-
pene (10 mg/kg, for 6 days, i.p) was effective in reducing D-
galactosamine/LPSs (D-GalN/LPS) (300 mg/kg and 30 μg/kg body
weight, respectively, i.p) resulting in a change in the activity of
aspartate aminotransferase (AST), alanine aminotransferase
(ALT), alkaline phosphatase (ALP), lactate dehydrogenase
(LDH), and serum gamma glutamyl transferase (γ-GT) in rats
[20]. Rafi and his colleagues demonstrated that LPS (0.5 μg/mL)
induced NO activity was inhibited by lycopene (1.25–10 μM)
 Protective effects of lycopene against LPS
TABLE 1

Protective
defense against Study design Protective agents Results Mechanism Ref.
LPS (100 ng/ml) Primary cultured Lycopene Suppressed Inhibition of ERK1/2 Shyu et al. [18]
microglia (5–20 μM) production of IL-1β,
TNF-α and NO
LPS (5 μg/ml) IEC-18 cells and TLE (100 μg/ml) Inhibited NF-kB Obstruction of IkBa Joo et al. [19]
splenocytes activity degradation, RelA
nuclear
translocation
D-GalN/LPS Male Wistar rat Lycopene Alterations to near Hepatoprotective Shivashangari
(300 mg/kg and (10 mg/kg, i.p) normal of γ-GT, action et al. [20]
30 μg/kg, i.p) AST, ALT, ALP,
LDH
LPS (0.5 μg/ml) Macrophage cell Lycopene Inhibition of NO Suppression of iNOS Rafi et al. [21]
lines (RAW 264.7) (1.25–10 μM) activity proteins and
mRNA expressions
LPS (100 ng/ml) Bone marrow Lycopene Inhibitor of DC Inhibition of MAPKs Kim et al. [22]
(BM)-derived maturation and NF-κB p65
murine myeloid DC translocation
RV and LPS Airway epithelial cell Pre-treatment Reduction in release Inhibition of Saedisomeolia
(1 μg/ml) (Calu-3) with lycopene of IL-6 and IP-10 formation of ROS et al. [23]
(2.5 μg/ml) and reduction in
activation of NF-κB
LPS (1 ng/ml) RAW 264.7 Lycopene (from Decreasing in Modulation of both Marcotorchino
Macrophages and 0.5 to 2 μM) expression of TNFα JNK and NF-κB et al. [24]
3 T3-L1 adipocytes signaling pathways
LPS (6 mg/kg) Sprague- Dawley rat Lycopene Reducing the Ameliorating LPS Liu and Chen
(5 mg/kg) expression of activated [25]
TNF-a and IL-6 and histopathological
inhibited the damages, enhance
stimulation of anti-oxidative
MAPK and NF-κB properties
pathway
LPS (1 mg/kg) Breeding hen Lycopene (20, 40, Increased HDL, T3, Antioxidant activity Sun et al. [26]
or 80 mg/kg, GSH/GSSG and
orally) immune organ
(thymus, bursal
and Fabricius)
index and
decreased TCHO,
BUN and LDL

through suppression of inducible nitric oxide synthase (iNOS)
and mRNA expressions in a mouse macrophage cell line model
(RAW 264.7) [21]. Additionally, lycopene was found to inhibit
LPS-stimulated dendritic cells (DC) maturation. The mechanism
by which lycopene suppressed the phenotypic and functional
maturation of murine dendritic cells (BM-DC) was attenuation
of mitogen-activated protein kinases (ERK1/2, p38, and JNk)
and NF-κBp65 translocation [22]. It has also been reported that
lycopene can inhibit the release of interleukin-6 (IL-6) and
interferon-gamma induced protein-10 (IP-10) in LPS and in rhi-
novirus (RV) infected airway epithelial cells (Calu-3). These
results suggest that lycopene has a potential role in inhibition of

Hedayati et al. 3

inflammation-induced by RV infection [23]. Lycopene also has
anti-inflammatory activity on RAW 264.7 macrophages by mod-
ulating the LPS (1 ng/mL) induced expression of TNF-α. The
proposed mechanisms are associated with a limit of macro-
phage migration, reduction of JNK and NF-κB signaling path-
ways, and the pro-inflammatory cytokines that are induced by
macrophage conditioned medium and chemokine mRNA
expression in 3 T3-L1 adipocytes [24]. Lycopene (5 mg/kg,
orally) has been reported to improve LPS (6 mg/kg, i.p) induced
histopathological damage, to enhance anti-oxidative properties,
to decrease the expression of TNF-α and IL-6 and to inhibit the
stimulation of mitogen-activated protein kinase (MAPK) and the
NF-κB pathway in acute lung injury (ALI) in rats [25]. The pro-
ject of Sun et al. focused on the effects of lycopene (20, 40, or
80 mg/kg, orally for 35 days) on biochemical factors, immune
organ profiles and antioxidant capacity in breeding hens after
LPS (1 mg/kg, on 35th day) stimulation. LPS increased high den-
sity lipoprotein (HDL) and triidothyronine (T3), increased the
glutathione to oxidized glutathione ratio (GSH/GSSG) and the
immune organ (thymus, bursal, and Fabricius) index. In con-
trast, pretreatment with lycopene reduced total cholesterol, low
density lipoprotein, and blood urea nitrogen [26].
These cell culture and animal studies show that Lycopene
supplementation affects inflammatory immune response to LPS
mainly via attenuation of ERK1/2, p38, JNk, and NF-κB signal-
ing pathways [22]. The dose ranges of lycopene in in vitro and
in vivo studies were 1.25–20 μM and 5–10 mg/kg respectively.
In future, clinical trials in human are needed to evaluate the
efficacy of lycopene in different inflammatory conditions.
Microcystin-LR
Microcystin-LRs (MC-LRs), a group of cyclic heptapeptide hepa-
totoxins, are produced by numerous species of cyanobacteria
such as Nostoc, Oscillatoria, Microcystis, and Anabaena [27,28].
MC-LRs act as serine/threonine protein phosphatases (PPs)
inhibitors resulting in hyperphosphorylation of functional pro-
teins [29,30]. Supplementation with lycopene (10 mg/mouse/d,
i.p. for 2 weeks) reduced ALT, total bile acids (TBA), and gluta-
thione S-transferase (GST) and increased glycogen and GPx) fol-
lowing microcystin-LR (75 μg/kg, single dose, i.p.) induced
toxicity in mouse liver. Consequently, lycopene supplementation
may have a protective role against microcysin-induced hepato-
toxicity [31].
2.3. Other toxins
D-Galactosamine
D-galactosamine causes hepatic necrosis by reducing the pool
of uridine in hepatocytes [32] which leads to inhibition of pro-
tein synthesis as well as messenger RNA (mRNA) [33]. Treat-
ment of rats with lycopene (10 mg/kg body weight/day, i.p, for
6 days) resulted in reduction of LPS/D-galactosamine (D-GalN/
LPS) (300 mg/kg and 30 μg/kg, i.p., of D-GalN and LPS, respec-
tively) induced oxidative stress. The protective activity of lyco-
pene is related to suppression of lipid peroxidation. In addition,
a protective effect of lycopene against D-GalN/LPS-stimulated
genotoxicity by free radicals attack was also observed [34].
4 lycopene against chemical and natural toxins
BioFactors
Shariff et al. recorded the lipoprotein concentrations of lipid
metabolizing-related enzymes, including lipoprotein lipase,
hepatic triglyceride (TG) lipase, and lecithin in the blood of D-
GalN/LPS (300 mg/kg and 30 μg/kg, respectively, i.p., 18 h
before the experiment) induced hepatitis in rats-fed lycopene
(10 mg/kg body weight, i.p., for 6 days) in the diet. These results
emphasized maintaining normal lipid metabolism as the basis
for the anti-oxidant role of lycopene [35].
3. Chemical induced toxicity
In this section, we discuss the important protective effects and
mechanisms of lycopene against a variety of chemicals includ-
ing metals, fluoride, pesticides, cardiotoxic, hepatotoxic, and
nephrotoxic agents (Fig. 1).
3.1. Metals
Cadmium
Cadmium is an environmental pollutant released into the atmo-
sphere from factories, urban traffic, incineration and other
industrial activities. It is deposited in the kidneys where it can
induce renal toxicity if not eliminated [36]. In one study, the
protective effects of lycopene (20 mg/kg body weight, i.p., for
15 days) against cadmium (0.32 mg/kg body weight, i.p, single
dose) induced renal toxicity was evaluated by studying renal
function in albino mice. Lycopene supplementation reduced
urea and creatinine concentrations and increased glycogen,
total protein and cholesterol [37]. Furthermore, lycopene
(20 mg/kg body weight, i.p., for 15 days) had a protective effect
against cadmium (0.32 mg/kg body weight, i.p.) induced oxida-
tive cardiac injury. Lycopene consumption decreased infarction
size and other morphological damage in cardic tissue of mice
[38]. Lycopene (10 mg/kg/day, orally) also has been reported to
protect against cadmium (6.6 mg/kg/day, orally, for 20 days)
induced lipid peroxidation (LPO) and body weight loss in rats. A
significant suppress in malondialdehyde (MDA) levels in plasma
and kidney homogenates as well as body weight loss were
observed in the lycopene supplemented groups [39].
It can be concluded that lycopene acts as a potential antiox-
idant that prevents cadmium-induced renal and cardiac toxicity
and weight loss in animal models via reducing of the oxidative
stress.
Copper
Copper, an essential part of several enzymes, is found in differ-
ent cells and tissues with the highest concentration in the liver.
Copper toxicity can results from oxidative stress and typically is
characterized by liver cirrhosis and/or injury of renal tubules
[40]. Interestingly, treatment of broiler chickens with lycopene
reduced triglycerides and LDL cholesterol concentration in
plasma, and suppressed the oxidation of LDL induced by cop-
per. Lycopene has a potential antioxidant activity [41]. Ghafari
et al. reported that lycopene caused an increase in radical for-
mation time in LDL and consequently reduced the susceptibility
of LDL oxidation induced by copper II [42].
 Lycopene as an abundant carotenoid, exhibit protective effects against several natural and chemical toxins which attributed to its
FIG 1 antioxidative and anti-inflammatory properties. Lycopene has positive effects on the anti-oxidants activity (GPX, SOD, and CAT)
and suppress the ROS generation pathways, and modify apoptosis pathways, thereby modulating inflammatory responses
(details have been explained in the text). Also, lycopene appears to reduce the D-Galactosamine/lipopolysaccharide and conse-
quent change in AST, ALT, ALP, LDH, and γ-GT levels. Its positive effects on MPTP-induced Parkinson disease through modula-
tion of Bcl-2, bax, and caspase cascades as biomarkers of apoptotic pathways briefly illustrated in figure. Furthermore, lycopene
exposure leads to upregulation of Nrf2 and HO-1 mRNA expression and downregulation in expression of NF-κB mRNA.Activating
sign: Blocking sign: GPX: glutathione peroxidase LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase ROS: reactive
oxygen species SOD: superoxide dismutase Nrf2: nuclear factor erythroid 2-related factor 2 NF-κB: nuclear factor kappa-light-
chain-enhancer of activated B cells AST: Aspartate transaminase ALT: Alanine transaminase ALP: Alkaline phosphatase LDH:
Lactate dehydrogenaseγ-GT: Gamma-glutamyltransferase HO-1: Heme oxygenase-1 LPS/GalN: Lipopolysaccharide/D-galactosamine

Mercury properties of lycopene (5, 10, 15, 20 mg/kg/day) against

Mercury is an toxic and rare heavy metal which is widely dis-
persed in nature by industrial activities [43]. Mercury accumu-
lates in the kidneys and can induce renal toxicity. Although
lycopene protected against renal toxicity caused by mercuric
chloride (5 mg/kg, body weight, s.c.) in rats by inhibiting lipid
peroxidation with selected anti-oxidant enzymes and by alter-
ing δ-aminolevulinate dehydratase (ALAD) activity, lycopene
(10–50 mg/kg, orally) did not suppress renal failure induced by
HgCl2 [44]. Lycopene has been reported to reduce Methyl mer-
cury (500 nM for 12 h) induced mitochondrial oxidative stress
in cultured cerebellar granule neurons (CGNs). Pre-treatment
with lycopene helped maintained cell viability and reduced lac-
tate dehydrogenase releases. ROS generation and accumulation
also were reduced by lycopene in the same cell system [45].
Hepatoprotective activity of lycopene (40 mg/kg, orally) against
mercuric chloride (2.2, 4.4, and 8.8 μmol/kg, s.c.) has been
reported in rats including: 1] suppression of reactive oxygen
species, 2] improvement of the function of superoxide dismu-
tase (SOD) and GSH-Px, and 3] reduction of ALT, LDH, MDA,
and GSH levels [43]. A micronucleus (MN) assay and histopath-
ological examination were used to determine the protective
mercury-stimulated cytotoxicity in albino mice. The results
showed that mercury (10 mg/kg body weight) caused degenera-
tion of hepatocyte, hemorrhage and degeneration of tubules in
the kidneys while lycopene treatment reversed or at least
reduced these effects. In addition, lycopene supplementation
had a protective effect on MN at 20 mg/kg/day [46].
Lead
Lead, a persistent toxic heavy metal, is a common industrial
and environmental pollutant. Lead exposure has been shown to
result in a wide variety of organ injuries, including damage to
the kidneys [47,48]. Ishiaq et al. in 2011 reported that con-
sumption of lycopene (33 g powdered tomato in water)
decreased the renal injury induced by lead in rats by improve
reduced GSHactivity. A summary of the protective effects of
lycopene against selected metals is provided in Table 2.
3.2. Fluoride
Fluoride is a monatomic anion of fluorine. It is added to several
consumer products including drinking water and toothpaste in
many countries. In the last century, the use of fluoride in food
industry has increased. Fluoride is naturally present in most

Hedayati et al. 5
 BioFactors

Protective effects of lycopene against heavy metals

TABLE 2

Protective defense
against Study design Protective agents Results Mechanism Ref.
Cadmium Albino mice Lycopene (20 mg/kg Reduced urea and Antioxidant Sharma and
(0.32 mg/kg, i.p) body weight, i.p) creatinine activities Vijaya [37]
concentration,
Increased
glycogen, total
protein and
cholesterol,
Prevented renal
toxicity
Cadmium Albino Mice Lycopene (20 mg/kg Decreased infarction Cardioprotective Sharma and
(0.32 mg/kg body body weight, i.p) size and effects Vijaya [38]
weight, i.p) morphological
damages
Cadmium (6.6 mg/kg/ Male Lycopene (10 mg/kg/ Suppressed MDA Antioxidant and Rencuzogullari
day, orally) Wistar-Albino day, orally) levels in plasma anti-inflammatory and Erdogan
rat and kidney activities [39]
homogenates,
Body weight loss
Copper Broiler chicken Lycopene (10 or Reduced triglyceride Antioxidant Lee et al. [41]
20 mg/kg),(17 g/kg and LDL activities
of tomato paste) cholesterol
concentration in
plasma,
Suppressed the
oxidation of LDL
Mercuric Chloride Rat Lycopene (40 mg/kg, Induced renal Hepatoprotective Deng et al. [43]
(2.2, 4.4, and orally) toxicity, Decreased effects
8.8 μmol/kg, s.c) ROS, GSH, and
MDA, elevated
SOD and GSH-Px
activities
Mercuric Chloride Male Wistar rat Lycopene Inhibited lipid Antioxidant Augusti
(5 mg/kg, s.c) (10–50 mg/kg, peroxidation, activities et al. [44]
orally) changed ALAD
activity, and
anti-oxidant
enzymes
Methyl Mercury Rat CGN cell Lycopene (0.5, 1, 5, Prevented Neuro protective Qu et al. [43]
(500 nM) line 10, 50, and 100 μM) mitochondrial effects
dysfunction,
Improved cell
viability, decreased
LDH release
Mercury (10 mg/kg Albino mice Lycopene (5, 10, Reduced Antioxidant Cavusoglu
body weight 15, 20 mg/kg/day) degeneration of activities et al. [46]
hepatocyte,
hemorrhage,
tubular in kidney

6 lycopene against chemical and natural toxins

 (Continued)
TABLE 2
Protective defense
against Study design Protective agents
Lead (200 g/ml, Wister rat Lycopene (33 g
orally) powdered tomato
in water)
seafood. Fluoride can easily pass from the plasma and is dis-
tributed in muscle and other organs [49]. Mansour et al. found
that fluoride (10.3 mg/kg body weight, for 5 weeks) induced
oxidative stress, reduced GSH levels, SOD activity and total
anti-oxidant capacity in rats (TAC) which was normalized by
supplementation with lycopene (10 mg/kg body weight, orally,
for 5 weeks) most probably due to the free-radical scavenging
and anti-oxidant function of lycopene [50].
3.3. Pesticides
Pesticides are designed to kill pests and include herbicides,
insecticides, rodenticides, and fungicides [51]. The extensive
application of pesticides for crop protection and agricultural
production can lead to public health and environmental pollu-
tion concerns.
Chlorpyrifos
Chlorpyrifos, a broad-spectrum organophosphorothioate insec-
ticide, has been widely used in both domestic and agriculture
applications [52]. Lycopene (10 mg/kg, body weight, orally) has
been reported to have a protective effect against chlorpyrifos
induced (0.04 mg/l, in their environment, for 14 days) changes
in certain hematological factors and on the oxidant/antioxidant
status of cells in fish [63].
Diazinon
Diazinon (DZN) is a wide-spectrum organophosphate insecticide
used for both agricultural and urban purposes [64]. Diazinon
has been shown to induce toxicity in various organs such as the
liver [53] and the nervous system [54,55]. It was shown that a
lycopene (10 mg/kg, for 14 days) and vitamin E (50 mg/kg, for
28 days) combination had a protective effect against DZN (0.76
and 2.3 mg/l) in fish. Dietary lycopene and vitamin E improved
selected hematological parameters and reduced the ALP, AST,
and ALT activity as well as the urea and creatinine concentra-
tions [56]. Moreover, the lycopene (10 mg/kg, for 14 days) and
vitamin E (50 mg/kg, for 28 days) combination supplied as a
dietary supplementation had a protective role against diazinon
toxicity (0.76 and 2.3 mg/l) in Oreochromis niloticus, a cichlid
fish. Consequently, lycopene appears to exerts its effects by
decreasing LPO and free-radicals in fish [57].
Hedayati et al.
Results Mechanism Ref.
Enhanced level of Antioxidant Patrick [47]
reduced activities
glutathione,
reduced level of
oxidized
glutathione
Deltamethrin
Deltamethrin, a synthetic pyrethroid type II pesticide containing
an α-cyano group, is used against a wide-spectrum of insects
including flies and mosquitoes [58]. The potential protective
effect of lycopene against deltamethrin (1.28 mg/kg/day, orally,
for 30 days) induced toxicity in kidney has been reported by El-
Gerbed et al. Deltamethrin exposure leads to enhancement of
the TNF-α factor, the number and atypical forms of mitochon-
dria, and ultrastructural lesions in the lining of cells in the
proximal tubules and changes in apical microvilli in rats. Sup-
plementation with lycopene (1 mg/kg per day) improved these
alterations in kidneys [59]. In addition, the effect of lycopene on
deltamethrin-stimulated (5 mg/kg/day body weight, orally) tes-
ticular damage in rats has been assessed. Results showed that
lycopene (1 mg/kg body weight) normalized body weight, serum
testosterone, total testicular oxidant capacity and poly (ADP-
ribose) polymerase (PARP) activity and reduced heat-shock
protein 70 (HSP-70) mRNA and DNA injury in rats [60]. Fur-
thermore, lycopene (10 mg/kg, orally) inhibited DNA injury and
thyroid gland toxicity induced by deltamethrine (2 mg/kg body
weight) in albino rats [61]. Lycopene (10 mg/kg, orally) provided
as a dietary supplement, appeared to have an important role in
the attenuation of deltamethrin (0.036, 0.018 μg/L, for 14 days)
induced oxidative stress in Cyprinus carpio by decreasing the
level of MDA and increasing SOD, CAT, and GSH-Px activi-
ties [62].
Malathion
Malathion is an organophosphate pesticides used widely to con-
trol pests because of its low toxicity and great selectivity for
insects [63]. Malathion intoxication is due to inhibition of acetyl-
cholinesterase activity in target tissues [64]. Malathion (0.5 and
1 mg/L, for 14 days) exposure in Cyprinus carpio carpio (carp)
resulted in changes in hematological parameters including red
blood cell (RBC) count, hemoglobin (Hb) concentration, hemato-
crit (Ht) and immune responses including white blood cell
(WBC) count, oxidative radical production [nitroblue tetrazo-
lium (NBT) activity), total plasma protein (TP) and total immu-
noglobulin (TI) levels, and phagocytic activity (PA)] as well as
inhibition of antioxidant capacity. In malathion exposed carps,
treatment with lycopene (10 mg/kg) resulted in normalization of
most of the above mentioned parameters [65].
7

Rotenone
Rotenone is a crystalline isoflavone which used as a pesticide. It
exists naturally in the seeds and stems of some plants [66]. It is
not particularly toxic to birds, mammals and humans. In con-
trast, rotenone is toxic for fish and exerts its toxic effect by
interfering with the mitochondrial electron transport system
[10]. A Parkinson-like disease model was employed to assess
the protective effect of lycopene (10 mg/kg body weight, orally)
against rotenone (3 mg/kg, body weight, i.p) induced oxidative
stress and neurobehavioral outcomes in C57BL/6 mice. The
results from this study suggested that the beneficial effects of
lycopene administration included increasing the SOD, CAT, and
GSH-Px activity [67]. Similar results were reported by Kaur
et al. in a rat model of Parkinson disease. Lycopene (10 mg/kg,
orally, for 30 days) supply its neuroprotective activity through
suppression of oxidative stress by normalizing parameters such
as GSH and SOD and by activating the complex-I (NADH Dehy-
drogenase) that has the potential to decrease free radical pro-
duction [68]. Thus, lycopene may be a candidate for treatment
of certain neurobehavioral abnormalities [68,69].
Cypermethrin
Cypermethrin, a synthetic type II pyrethroid, widely used as an
insecticide instead of organophosphorus and organochlorine to
control pests [70,71]. It has been demonstrated in Cyprinus car-
pio fish that the SOD, CAT, GSH-Px activity, and GSH concentra-
tion in blood and tissues were modified by cypermethrin (0.202,
0.404 μg/L in their environment for 28 days) exposure. Lyco-
pene (10 mg/kg body weight, orally, for 28 days), a naturally
antioxidant, could decrease MDA level in plasma as well as nor-
malized SOD, CAT, GSH-Px and GSH levels, by improving the
antioxidant defense system [72].
3.4. Herbicides
Herbicides are widely used for controlling undesirable weeds [73].
Atrazine
Atrazine, a triazine herbicide, is commonly used for control of
grassy weeds in maize, sorghum and sugarcane. Atrazine func-
tions as a photosynthesis blocker. It is a potential pollutant of
surface and ground water [74]. It has been reported that lyco-
pene (10 mg/kg/day, orally, for 4 weeks) administration in rats,
has a protective effect against oxidative damage in the adrenal
cortex induced by atrazine (300 mg/kg/day, orally, for 4 weeks)
through restoration of antioxidant defense and alteration of the
Nrf2/HO-1 signaling pathway reducing both NF-κB and
caspase-3 gene expression [75]. It also has been suggested that
lycopene (5 mg/kg, orally, for 21 days) has a hepatoprotective
effect on liver injury induced by atrazine (50 or 200 mg/kg,
orally, for 21 days) in mice. This protective effect has been sug-
gested to be exerted via regulation of the ionic homeostasis dis-
order through modulation of ATPase activity and subunits (1a1,
1b3, 1b4, and 2b4) transcription [76]. Moreover, similar studies
have reported the potential protective effect of lycopene
(5 mg/kg, orally, for 21 days) against atrazine (50 or 200 mg/kg,
orally, for 21 days) stimulated cardiotoxicity in a mouse model
8 lycopene against chemical and natural toxins
BioFactors
[77]. Nan Li et al. showed that supplementation of mice with
lycopene regulated NO production, inactivated the Tumor
necrosis factor receptor-associated factor 6 (TRAF6-NF-kB)
pathway as well as up-regulated TNF-α, IL-6, cyclooxygenase
2 (COX-2), and IL-1β and down-regulated the transforming
growth factor beta 1 (TGF-β) [78]. In addition, lycopene has
been reported to have a hepatoprotective effect against atrazine
induced increases in total cytochrome b5 (Cyt b5) in male Kun-
ming mice. Lycopene (5 mg/kg, orally, for 21 days) administra-
tion to male Kunming mice modulated the activity of hepatic
CYP450s enzymes and normalized the expression of four
CYP450s genes for CYP1b1, CYP2a4, CYP2e1, and CYP4A14
[79]. In another study in rats, the protective effect of lycopene
against oxidative stress and autophagy induced by atrazine was
investigated. In this study, lycopene inhibited the activation of
autophagy including LC3II/LC3I ATGs, Belin, and p62 through
Nrf2 signaling pathway activation [80].
The evidences presented here, indicate the protective role
of lycopene against pesticides toxicity. Administration of lyco-
pene as one of the most effective antioxidants in the carotenoid
family, ameliorates pesticides-induced oxidative stress by
decreasing lipid peroxidation and by altering the antioxidant
defense system. Other mechanisms including modulation of the
activity of hepatic CYP450s enzymes and regulation of immune
system activity are also involved. Although, more investigations
are necessary to elucidate the exact mechanism of lycopene-
mediated protection against pesticide toxicity and the potential
usefulness of this compound.
3.5. Cardiotoxic agents
Doxorubicin
Doxorubicin (DOX), a chemotherapeutic agent, is in antitumor
antibiotic family of drugs which interferes with DNA function.
Severe side effects include allergic reactions, renal toxicity, and
treatment-related leukemia has been reported in patients
receiving DOX [93]. The major side effects, however, is cardio-
toxicity which may result in congestive heart failure [81]. In one
study, the effects of tomato extract (1.2 and 2.4 g/kg, i.p.) and
lycopene (1.7 and 3.5 mg/kg, i.p) on DOX (15 mg/kg, single dose,
i.p) stimulated myocardial toxicity were investigated in mice.
Treatment with lycopene as well as an aqueous tomato extract
was cardioprotective apparently by reducing creatine phospho-
kinase (CPK) activity thus improving cardiac inflammation [82].
Echocardiogram and morphological examinations showed that
doxorubicin (4 mg/kg, body weight, i.p) induced myocyte injury
in male Wistar rats which was significantly inhibited by lyco-
pene (5 mg/kg/day, body weight, orally, a 7-week period) with-
out preventing accumulation of interstitial collagen. Also,
lycopene had no effects on cardiac dysfunction [83]. Yilmaz
et al. determined the effects of lycopene (4 mg/kg, orally) on
Adriamycin (trade name for doxorubicin) (10 mg/kg, i.p)
induced cardiotoxicity and nephrotoxicity. Their findings indi-
cated that post-injection treatment with lycopene normalized
creatinine and urea levels in plasma. The MDA, GSH and CAT
activities also were normalized and no histopathological
 Protective effects of lycopene against pesticides
TABLE 3

Protective defense
against Study design Protective agents Results Mechanism Ref.
Chlorpyrifos (0.04 mg/l, Cyprinus Lycopene (10 mg/kg, Alterationed in Antioxidant Ural [63]
in their environment) carpio orally) hematological factors activities
carpio consist of the Hb and
Ht levels, RBC, WBC
counts and oxidant/
antioxidant balance,
improved SOD, CAT,
and GSH-Px activity
Diazinon (0.76 and Oreochromis Lycopene (10 mg/kg) Altrated hematological Antioxidant Ibrahim and
2.3 mg/l) niloticus and vitamin E parameters and activities Banaee
(50 mg/kg) reduced ALP, AST, [56]
and ALT avtivity as
well as urea and
creatinine
concentrations
Diazinon (0.76 and Oreochromis Lycopene (10 mg/kg, Decreased in LPO and Antioxidant Ibrahim [57]
2.3 mg/l) niloticus for 14 days) and vit E free-radical activities
(50 mg/kg, for inactivating
28 days)
Deltamethrin Male albino Lycopene (1 mg/kg, Decreased the serum Nephroprotective El-Gerbed
(1.28 mg/kg/day, rat orally) TNF-α, prevented effects et al. [59]
orally) glomerular
hypertrophy, and
reduced capsular
space enlargement
Deltamethrin (5 mg/kg, Wistar rat Lycopene (1 mg/kg Normalized body Antioxidant Ismail and
orally) weight, serum activities Mohamed
testosterone, [60]
testicular total
oxidant capacity
levels and poly
(ADP-ribose)
polymerase (PARP)
activity and reduce in
HSP-70, mRNA, and
DNA injury
Deltamethrin (0.036, Cyprinus Lycopene (10 mg/kg, Decreased the level of Antioxidant Yonar and
0.018 μg/L, orally) carpio orally) MDA and increased activity Sakin [62]
the SOD, CAT, and
GSH-Px activities
Malathion (0.5 and Cyprinus Lycopene (10 mg/kg, Normalized RBC Antioxidant Yonar [72]
1 mg/L carpio orally) concentrations, Hb activities
and Ht levels, SOD,
MDA, CAT, GSH-px,
GSH levels

Hedayati et al. 9
 BioFactors

(Continued)
TABLE 3

Protective defense
against Study design Protective agents Results Mechanism Ref.
Rotenone (3 mg/kg C57BL/6 mice Lycopene (10 mg/kg Increased the SOD, Antioxidant Liu
body weight, i.p) body weight, orally) CAT, and GSH-Px activities et al. [67]
activity
Rotenone (3 mg/kg Wistar rat Lycopene (10 mg/kg Normalizied the Antioxidant Kaur
body weight, i.p) body weight, orally) antioxidant activities et al. [68]
parameters such as
GSH and SOD as well
as activated the
complex-I (NADH
Dehydrogenase)
Cypermethrin (0.202, Cyprinus Lycopene (10 mg/kg Decrease MDA level in Antioxidant Yonar [65]
0.404 μg/L in their carpio body weight, orally) plasma as well as activities
environment) normalized SOD,
CAT, GSH-Px, and
GSH levels

alterations were reported in heart and kidneys [84]. It has been
reported that tomato-oleoresin (5 mg/kg, body weight, orally)
has a protecting affect against DOX (4 mg/kg, body weight, i.p)
induced cardiac oxidative DNA damage. In this report, DOX
maintained lycopene levels in the myocardium of lycopene-
supplemented rats and the induced cardiac myocytes DNA
damage was reduced by the tomato-oleoresin supplementation.
However, the DOX induced cytotoxicity and mortality were not
reduced by the tomato-oleoresin supplementation [85].
In conclusion, the protective effects of Lycopene against
DOX-induced heart toxicity have been showed in four animal
studies. However, before a conclusive statement on the poten-
tial usefulness of lycopene as an adjunct therapy to DOX, there
is a need for more studies, including human trials.
Isoproterenol
Isoprenaline, or isoproterenol, is a non-selective β adrenorecep-
tor agonist which used for cure of bradycardia, heart blockage,
and sometimes for asthma. In large doses, isoproterenol (ISO)
has been reported to cause myocardial infarction [86,87].
Mohamadin et al. [4] have shown that dietary lycopene
(4 mg/kg, orally, once daily for 21 days) had a protective effect
on the cardiotoxicity induced by ISO in rats (85 mg/kg, s.c., once
daily for 2 days). Results from this study showed that the lyco-
pene supplement fed to ISO rats improved lysosomal injury,
modified alterations in the lipid profile and in the oxidative
stress markers and the activity of AST, LDH, creatine kinase-
MB (CK-MB), and cardiac troponinT(cTnT), biomarkers of car-
diacotixicity, were decreased. Upagenlawar et al. showed that
in rats with ISO (200 mg/kg, s.c., for 2 days) induced myocardial
infarction there was a decrease in caspase 3 protease function
and DNA injury in rats fed lycopene (10 mg/kg/day, orally, for
30 days). Lycopene supplementation reduced CRP levels and
MPO activity indicating a potential anti-inflammatory role for
lycopene. In addition, lycopene improved the hemodynamic
profile including diastolic, systolic, and mean blood pressure.
As a result, it has been suggested that lycopene may have bene-
ficial effects in the treatment of ISO-induced myocardial infarc-
tion. (Table 3) [88].
3.6. Protective effect of lycopene against various
neurotoxic agents
Glutamate
Glutamate is a neurotransmitter. Characterized receptors for
glutamate belongs to three major classes, AMPA, NMDA, and
metabotropic glutamate receptors. Another class of receptors,
kainate receptors, are similar in many respects to AMPA recep-
tors. The central nervous system induced toxicity of glutamate
is related to production of ROS [89]. The effects of lycopene
(10 mg/kg, body weight/day, for 4 weeks) on neurotoxicity
induced by monosodium glutamate (5 mg/kg, body weight/day,
for 4 weeks) in rats were investigated. In the lycopene-treated
group, the oxidative injury, lipid peroxidation levels, the bio-
chemical serum profile (LDH, CPK, and CPK-BB) and cholines-
terase activity were repaired. Lycopene also protected against
monosodium glutamate-induced brain tissue damage by sup-
pressing apoptosis indicating inhibition of down-regulation of
Bcl2 [5].
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent
neurotoxicant, causes Parkinson disease in man and non-
human primates [90]. MPTP is converted to MPP1 (1-methyl-
4-phenylpyridinium) by monoamine oxidase B which induces

10 lycopene against chemical and natural toxins

dopaminergic cells damage [91]. It has been reported that lyco-
pene (5, 10, and 20 mg/kg/day, orally) reduced symptoms in a
mouse Parkinson disease model induced by MPTP (30 mg/kg
body weight, i.p) by increasing Bcl-2 and decreasing bax, cas-
pase 3, 8, and 9, markers of apoptosis signaling pathways.
Lycopene also has been reported to have a protective effect on
striatal dopamine (DA) and its metabolites following induction
by MPTP. In addition, lycopene suppressed oxidative stress and
motor abnormalities in the same mouse mode [9]. Yi et al.
reported the effects of lycopene (0.5, 1.0, 2.0, or 4.0 μM for 2 h)
against MPP1 (500 μM for 24 h) induced cytotoxicity in human
neuroblastoma SH-SY5Y cells. These data suggested that lyco-
pene evokes its protective effects by improving mitochondrial
dysfunction, apoptosis and by decreasing the accumulation of
ROS as well as LPO levels [92].
6-Hydroxydopamine
6-Hydroxydopamine, a synthetic neurotoxic agent, exerts its
effects by activation of the Fenton reaction which leads to pro-
duction of free radicals [93]. The protective effect of lycopene
on 6-Hydroxydopamine (1 μg/μl injected into the SNc) stimu-
lated neurotoxicity in a rat model of Parkinson disease(PD)
might be associated with suppressing the degeneration of
dopamine-including neurons in the substantia nigra pars com-
pacta (SNc) [94].
Amyloid β
Amyloid beta (Aβ) peptide constitutes the main component of
senile plaques. This protein which is involved in the neuropa-
thology of Alzheimer disease [95] is toxic to the nervous system.
Oxidative stress-related to one or several apoptotic pathways
has been suggested as a possible mode of action [96]. Lycopene
(0.1, 0.5, 1, 2, or 5 μM, for 4 h) added to medium containing cul-
tured rat cortical neurons reduced ROS and mitochondrial
superoxide production that had been induced by Aβ (10 μM)
[97]. The data further suggested that lycopene (0.1–10 μM for
4 h) may play a protective role against the neurotoxicity
induced by β-Amyloid (25 μM) via suppression of oxidative
injury. Lycopene also increased the expression of antiapoptotic
Bcl-2, reduced the expression of proapoptotic Bax, and inhib-
ited the activation of caspase-3 [96].
3.7. Protective effect of lycopene against the various
hepatotoxic agents
Acetaminophen
Acetaminophen (N-acetyl-p-aminophenol, APAP) is an analgesic
and antipyretic drug. Liver damage including hepatic necrosis
and acute liver failure is caused by overdoses of APAP [98]. It
has been shown that lycopene (in a dose-dependent manner,
orally) protects against acetaminophen (500 mg/kg, orally)
induced liver injury in C57BL/6 mice by ameliorating the redox
state and by decreasing LPO markers including thiobarbituric
acid reactive substances and the expression of IL-1b and by
increasing MMP-2 (gelatinase A) activation and anti-oxidant
enzymes including CAT and GSH [99]. Moreover, supplementa-
tion with lycopene (10 or 100 mg/kg, orally) appeared to be
Hedayati et al.
effective in altering GSSG, GSHT and CAT levels. Supplementa-
tion with lycopene decreased oxidative stress which could be
related to a reduction in protein carbonylation in acetamino-
phen (500 mg/kg, orally) induced hepatotoxicity in C57BL/6
mice. Lycopene has also been reported to suppress production
of ROS in SK-Hep1 cells [6].
Carbon tetrachloride
Carbon tetrachloride (CCl4) causes liver injury in experimental
animals which is associated with its metabolite CCl3 as a free
radical that leads to lipid peroxidation [100]. In the study by
Pinto et al., it was shown that lycopene (0.35, 0.65, 1.30 mg/kg,
body weight, orally) was chemoprotective against carbon tetra-
chloride (2.5 ml/kg i.p) induced acute liver damage in rats. A
significant increase was observed in the activity of SOD, CAT
and GPx and the concentration of GSH, with a reduction in
lipoxygenase activity in lycopene-treated rats [101].
2,3,7,8-tetrachlorodibenzo-p-dioxin
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a polychlorinated
aromatic hydrocarbon, is a known human carcinogen and an
hepatic toxicant [102]. In this regard, the effects of lycopene
(20 μM, for 1 h) against liver microsomal toxicity induced by
2,3,7,8-tetrachlorodibenzo-p-dioxin (15 nM for 1 h) were evalu-
ated in rat liver. TCDD decreased LPO and H2O2 production,
regulated thiol and carbonyl content and reversed the profiles
of superoxide dismutase, GPx, CAT, glutathione-S-transferase,
and GSH [103].
3.8. Protective effect of lycopene against
nephrotoxicants
Gentamicin
Gentamicin, an aminoglycoside antibiotic, is widely used
against gram negative bacteria [104]. The nephrotoxicity of
gentamicin has been related to hydroxyl radicals and oxidative
stress [105]. Pre-treatment with lycopene (4 mg/kg/day) had no
effect on the biochemical and oxidative stress profile in genta-
micin (100 mg/kg/day) treated rats; however, simultaneous
treatment with lycopene reduced the urea and creatinine levels
and markedly increase GSH, GSH Px, and CAT [8].
Cisplatin
Cisplatin is a potent antineoplastic drug. The untoward effects
of cisplatin include chromosomal damage [106], hepatotoxicity
[107], and nephrotoxicity [108]. Cisplatin can elevate the
inflammatory response, oxidative stress and renal vasculature
injury as well as diminished glomerular filtration [109] in
human. In one study in rats, the effects of lycopene (6 mg/kg,
body weight, orally) on cisplatin (7 mg/kg, body weight, i.p)
induced nephrotoxicity was evaluated. Lycopene decreased
serum urea and creatinine levels. A reduction in efflux trans-
porters MRP2 and MRP4 and upregulation of OAT1, OAT3,
OCT1, and OCT2 also was observed after lycopene exposure [7].
Similar studies have showed that lycopene can decreased
inflammation by suppression of NF-κB P65, and attenuated
nephrotoxicity induced by cisplatin through modulating of the
Nrf2/HO-1 signaling pathway [110].
11
 BioFactors

Protective effects of lycopene against the various agents induced organ toxicity
TABLE 4

Protective defense
against Study design Protective agents Results Mechanism Ref.
Cardiotoxicity
Dox (15 mg/kg, Albino Balb/c Lycopene (1.7 and Reduced CPK activity Scavenging free Karimi
i.p) mice 3.5 mg/kg, i.p) and improved radicals and thus et al. [82]
cardiac blocking the lipid
inflammation and chain reaction
injury, inhibited
lipid peroxidation
Adriamycin Sprague–Dawley Post-injection Normalized creatinine Antioxidant effects Anjos
(10 mg/kg, i.p) rat treatment with and urea levels in Ferreira
lycopene (4 mg/kg, plasma, MDA, GSH, et al. [83]
orally) and CAT activities
and
histopathological
altrations in heart
Dox (4 mg/kg, Male Wistar rat Tomato-oleoresin Protection effects Antioxidant effects Ferreira
body weight, (5 mg/kg, body against cardiac et al. [85]
i.p) weight, orally) myocytes DNA
damage
Isoproterenol Sprague–Dawley Lycopene dietary Improved lysosomal Inactivation of Mohamadin
(85 mg/kg, s.c) rat (4 mg/kg, orally) injury, alterations in free-radical activity et al. [4]
lipid profile, and its antioxidant
oxidative stress effects
markers and the
activities of AST,
LDH, creatine
kinase-MB (CK-MB),
and cTnT
Isoproterenol Albino rat lycopene (10 mg/kg/ Reduced CRP levels Anti-inflammatory Upaganlawar
(200 mg/kg, s. day, orally) and MPO activity effects et al. [88]
c)
Neurotoxicity
Monosodium Albino Wistar Pretreatment with Decreased the Antioxidant activity Sadek
glutamate rats lycopene (10 mg/kg, expression of Bax and antiapoptotic et al. [5]
(5 mg/kg, s.c) orally) and increased the effects
expression of Bcl-2,
inhibited the
activation of
caspase-3
MPTP C57bL/6 mice Lycopene (5, 10 and Increased Bcl-2 and Antioxidant and Prema
(30 mg/kg, i.p) 20 mg/kg, orally) decreased bax, antiapoptotic et al. [9]
caspase 3, 8, and 9 properties

12 lycopene against chemical and natural toxins

 (Continued)
TABLE 4

Protective defense
against Study design Protective agents Results Mechanism Ref.
MPP (500 μM)
+
Human Lycopene (0.5, 1.0, Improved cell viability Improved Yi et al. [92]
neuroblastoma 2.0, or 4.0 μM) and decreased mitochondrial
SH-SY5Y cell apoptotic rate, function
suppressed the
ROS accumulation,
and LPO
6-OHDA (1 μg/ Fischer 344 rat Lycopene Increase striatal DA Antioxidant di Matteo
μl) and DOPAC levels properties et al. [94]
Aβ (10 μM) Cultured rat Lycopene (0.1, 0.5, Reduced ROS and Inhibiting Qu et al. [97]
cortical 1, 2, or 5 μM) mitochondrial mitochondrial
neurons superoxide oxidative stress and
production improving
mitochondrial
function
Aβ (25 μM) Cultured rat Lycopene (0.1–10 μM) Increased the Inhibiting oxidative Qu et al. [96]
cortical neuron expression of c stress and
Bcl-2, reduced the apoptosis
expression of Bax
and inhibited the
activation of
caspase-3
Hepatotoxicity
Acetaminophen C57BL/6 mice Lycopene (in a Decreased LPO Antioxidant effect Bandeira
(500 mg/kg, dose-dependent marker, including et al. [6]
orally) manner, orally) thiobarbituric acid
reactive substances,
expression of IL-1b,
and increased the
MMP-2 activation
Acetaminophen C57BL/6 mice Lycopene (10 or Decrease GSSG, Antioxidant effect and Bandeira
(500 mg/kg, And SK-Hep1 100 mg/kg, orally) oxidative stress and reduce in protein et al. [99]
orally) cells normalized GSHt carbonylation
and CAT enzymes
Carbon Wistar rat Lycopene (0.35, 0.65, Increased the activity Antioxidant effect Pinto
tetrachloride 1.30 mg/kg, orally) of SOD, CAT, GPx, et al. [101]
(2.5 ml/kg, i.p) GSH, and reduced
the LOX activity
TCDD (15 nM) Albino rat Lycopene (20 μM) Decreased LPO and Antioxidant effect Aly
H2O2 production, et al. [103]
regulated thiol and
carbonyl content,
reversed
anti-oxidant profiles

Hedayati et al. 13
 BioFactors

(Continued)
TABLE 4

Protective defense
against Study design Protective agents Results Mechanism Ref.
Nephrotoxicity
Gentamicin Sprague–Dawley Simultaneous Reduced urea and Antioxidant activities Karahan
(100 mg/kg, i. rats treatment with creatinine levels et al. [8]
p) lycopene (4 mg/kg, and increased GSH,
orally) GSHPx, and CAT
Cisplatin Wistar rat Lycopene (6 mg/kg, Decreased urea and Nephroprotective Erman
(7 mg/kg, i.p) orally) creatinine in serum, effects et al. [7]
MRP2 and MRP4,
upregulation of
OAT1, OAT3, OCT1,
and OCT2
Cyclosporine A Sprague–Dawley Lycopene (10 mg/kg, Decreased urea and Antioxidant activities Ateşşahin
(15 mg/kg, i.p) rat orally) creatinine in plasma et al. [113]
as well as
ameliorated tubular
degeneration,
necrosis, thickened
basement
membranes, and
inter-tubular
fibrosis
Cyclosporine A Swiss albino rat lycopene (40 mg/kg, Decreased serum Antioxidant activities Gado and
(15 mg/kg, i.p) orally) concentration of Adam [114]
urea and creatinine,
increased the SOD,
and GPx and
suppressed the rise
of MDA
Colistin Kunming mice Cotreatments with Up-regulated Nrf2 Antioxidative Dai
(15 mg/kg, i.v) lycopene (20 mg/kg, and HO-1 mRNA property et al. [116]
orally) expression and
downregulated the
expression of NF-ĸB
mRNA
Adriamycin Sprague–Dawley Lycopene (4 mg/kg, Normalized CAT Antioxidant activities Yilmaz
(10 mg/kg, i.p) rat orally) activity, creatinine, et al. [84]
and urea levels,
tubular necrosis,
cloudy swelling of
the tubular
degeneration, large
hyaline casts in
tubular lumen,
tubular dilatation
glomerular
congestion, and
intertubular
haemorrhagia

14 lycopene against chemical and natural toxins

Cyclosporine a
Cyclosporine A (CsA) is a lipophilic compound which is used as
an immunosuppressive agent after transplantation and in the
treatment of autoimmune diseases [111]. One of the side effects
of CsA, nephrotoxicity, limits it use [112]. As an anti-oxidant,
lycopene may have a protective effect on CsA stimulated oxida-
tive stress and renal injury. Lycopene has been reported to
decrease urea and creatinine in the plasma and to ameliorated
tubular degeneration, necrosis, inter-tubular fibrosis and thick-
ening of the basement membrane in rats [113]. In addition, the
use of lycopene (40 mg/kg/day, orally, for 5 days before and
10 days concomitant with CsA injection) in rats, reduced renal
injury induced by CsA (15 mg/kg/day, i.p, for 10 days) as sug-
gested by a decrease in the serum concentrations of urea and
creatinine, the increase in SOD and GPx and the suppression of
MDA. In addition, lycopene restored the GSH content in kidney
tissue [114].
Colistin
The clinical use of colistin, a polymyxin glycopeptide antimicro-
bial agent produced by certain strain of Bacillus polymixa
[115], is limited because of its nephrotoxicity [130]. Co-
treatment of colistin (15 mg/kg/day, i.v.) with lycopene
(20 mg/kg/day, body weight, orally) in mice, significantly up-
regulated Nrf2 and HO-1 mRNA expression and down regulated
the expression of NF-κB mRNA which can functions as a free
radical and singlet-oxygen scavenger in renal toxicity. These
data suggest that lycopene might have some protective effect
against colistin induced nephrotoxicity [116].
Methotrexate
Methotrexate (MTX), a class of antifolates, is widely used as an
anti-cancer and immunosuppressive drug in the treatment of
malignancies and inflammatory diseases. The nephrotoxicity
caused by MTX has been attributed to oxidative stress and
inflammation [117]. Oguz et al. showed that lycopene (10 mg/kg,
orally) and melatonin (40 mg/kg. i.p) treatment decreased NO
levels in rats suffering from renal injury induced by MTX
(20 mg/kg, i.p). The histopathological evaluation indicated that
there was significant improvement in the tubular dilation and
cell swelling. These protecting effects against renal injury
induced by MTX may be associated with the antioxidant and
anti-inflammatory actions of lycopene [118]. Table 4 represents
the effects of lycopene against organtoxic agents in reported
previous studies.
4. Clinical studies
Several clinical trials have suggested that lycopene reduces bio-
markers of lipid peroxidation and protein oxidation. For exam-
ple, lycopene supplementation decreased DNA injury, protein
and LDL oxidation in healthy volunteers. It also was reported to
decrease LDL oxidation in Type 2 diabetic subjects and to
reduce prostate-specific antigen (PSA), tumor burden and
increase gene expression of connexin in patients with prostate
Hedayati et al.
cancer [119]. The effects of lycopene on the progression of pros-
tate cancer have been studied [120–122]. In a 1999 placebo-
controlled trial, 578 men with developed prostate cancer were
followed for 13 years. Gann et al. measured five major plasma
carotenoid peaks [a- and b-carotene, b-cryptoxanthin, lutein,
lycopene, and retinol] with HPLC. With increasing quintile of
plasma lycopene (5th quintile OR 5 0.75, 95% CI 5 0.54–1.06;
P trend 5 0.12), the odds ratio for all prostate cancers declined
slightly. There was an inverse association for aggressive pros-
tate cancers (5th quintile OR 5 0.56, 95% CI 5 0.34–0.91; P,
trend 5 0.05) [123]. Kucuk and his colleagues designed a Phase
II randomized clinical trial of lycopene supplementation prior
to radical prostatectomy. Twenty six men with localized pros-
tate cancer received twice daily 15 mg of lycopene for 3 weeks
before radical prostatectomy. Insulin-like growth factor 1 (IGF-
1), IGF binding protein-3, prostate-specific antigen and plasma
levels of lycopene were measured at baseline and after 3 weeks.
The result showed that prostate-specific antigen levels
decreased by 18% and the expression of connexin 43 in cancer-
ous prostate tissue was increased compared to control group
[124]. In another study to clarify the efficacy of lycopene and
soy isoflavones on serum PSA levels in men who developed
prostate cancer, lycopene and soy isoflavones were reported to
delay the development of hormone-sensitive and hormone-
refractory prostate cancer [125]. Lycopene has been shown to
have an effect on cardiovascular disease (CVD) risk factors
including inflammation, oxidative stress, blood pressure, lipid
metabolism, and endothelial function [126,127]. A meta-
analysis suggested that 25 mg/day lycopene consumption lead
to LDL cholesterol reduction of about 10% compared to low
doses of statins [141]. The overall summary of 1189 publica-
tions indicated that a tomato intervention was associated with
significant reductions in LDL-cholesterol and IL-6, flow-
mediated dilation (FMD) improvement and reduced systolic
blood pressure. Moreover the available evidence on the effects
of lycopene supplementation on CV risk factors supports the
view that increasing the intake of lycopene has a positive effect
on blood lipids, blood pressure and endothelial function [144].
In a recent systematic review and meta-analysis, it was
reported that the highest consumption category with the high-
est serum concentration of lycopene had significantly lower risk
of stroke (26%), mortality (37%), and CVDs (14%), but limited or
no association of lycopene with atherosclerosis, congestive
heart failure or atrial fibrillation. Lycopene was not significantly
associated with myocardial infarction [128].
Hereafter, more reliable clinical trials, consisting of well-
designed clinical trials, are clearly necessary using larger and
longer studies to better delineate the therapeutic role of Lyco-
pene in human.
5. Conclusion
Various in vitro, in vivo, and clinical studies investigating the
protective effect of lycopene against a variety of toxicants
15

suggest potential protective effects of lycopene against myco-
toxins, bacterial toxins, metals, fluoride, pesticides, cardiotoxic,
neurotoxic, hepatotoxic, and nephrotoxic chemical agents. The
protective impact of lycopene was principally attributed to its
anti-oxidative, free-radical scavenging, chelating and anti-
apoptotic properties, each of which has the potential to modify
the inflammatory response. However, more clinical trials are
required to verify the efficacy of lycopene in human as a protec-
tive agent against these inflammatory responses.
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