research article

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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Antidotal or protective effects of Curcuma longa (turmeric) and its active
ingredient, curcumin, against natural and chemical toxicities: A review
Azar Hosseinia
, Hossein Hosseinzadehb,⁎
a
Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad Iran
b
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
A R T I C L E I N F O
Keywords:
Curcuma longa
Curcumin
Natural toxins
Chemical toxins
Protective effects
Toxicology
A B S T R A C T
Curcuma longa is a rhizomatous perennial herb that belongs to the family Zingiberaceae, native to South Asia and
is commonly known as turmeric. It is used as herbal remedy due to the prevalent belief that the plant has medical
properties. C. longa possesses different effects such as antioxidant, anti-tumor, antimicrobial, anti-inflammatory,
wound healing, and gastroprotective activities. The recent studies have shown that C. longa and curcumin, its
important active ingredient, have protective effects against toxic agents. In this review article, we collected in
vitro and animal studies which are related to protective effects of turmeric and its active ingredient against
natural and chemical toxic agents.
1. Introduction
Nowadays, herbal medicines are used in different diseases. The re-
cent studies have shown some plants including black cumin [1], saffron
[2], barberry [3] and green tea [4] have antidotal or protective effects
against toxic agents in different tissues. Curcuma longa (turmeric), na-
tive to tropical South Asia, belongs to the Zingiberaceae family. There
are about 133 species of C. longa in worldwide. Turmeric is used in
food, cosmetic and pharmaceutical industries. More than 100 active
compounds are found in this herb. The root is composed of volatile oil
such as turmerone and coloring ingredient which is known to curcu-
minoids [5]. The d-α-phellandrene, cinol, d-sabinene borneol, sesqui-
terpenes and zingiberene are identified as volatile oil [6]. Curcumin, as
curcuminoids, is an important compound in turmeric. It has different
biological activities such as antioxidant [7], anti-carcinogenic [8,9] and
anti-inflammatory activity [10,11]. The most of pharmacological ef-
fects of turmeric are related to the presence of curcumin which has anti-
oxidant activity. In vivo and in vitro studies have shown that this herb
has different pharmacological effects. In folk medicine, turmeric is used
for respiratory diseases such as allergy, liver problems, sinusitis and
anorexia [12]. Nowadays other effects have identified from this med-
icinal herb such as anticancer [13,14], cardioprotective [15], hepato-
protective [16,17], antiarthritic properties [18] and hypoglycemic
[19]. Also it is applied in oral cancer, skin cancer [20], stomach cancer
[21] and metabolic syndrome [22]. The studies have reported the
protective effects of C. longa and its active components against toxic
agents in different tissues such as liver [23], brain [24] and
cardiovascular system [25].
2. Methods
In this review article, we collected different research projects in
scientific databases such as MEDLINE, Scopus, Web of Science data-
bases and local references, which study the protective or antidotal ef-
fects of C. longa and its major components against natural toxins and
chemical-induced toxicity. Studies were identified through electronic
databases from their inception up to Jun 2017. The keywords for the
search were: Curcuma longa, turmeric, curcumin, natural toxin, anti-
dote, chemical toxin and protective effects.
3. Natural toxins
According to recent studies, C. longa or curcumin has antidotal ef-
fects against some natural toxins in different organs.
3.1. Aflatoxin
3.1.1. Nephroprotective
Aflatoxins (AFs) as mycotoxin are produced by Aspergillus species.
The four major forms of aflatoxin including B1, B2, G1, and G2 which
aflatoxin B1 has more toxicity than other aflatoxins [26]. The toxicity of
aflatoxins is appeared as hemorrhage, growth retardation, heart and
kidney, damage to liver, and death [27,28]. Aflatoxin increased urea,
Cr and uric acid while decreased total protein levels. It causes dilation
https://doi.org/10.1016/j.biopha.2018.01.072
Received 26 September 2017; Received in revised form 11 January 2018; Accepted 11 January 2018
⁎
Corresponding author at: Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran.
E-mail address: Hosseinzadehh@mums.ac.ir (H. Hosseinzadeh).
Biomedicine & Pharmacotherapy 99 (2018) 411–421
0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
T

2. of capillaries, enlargement of glomeruli and necrosis. It increased pro-
apoptotic proteins such as bax and caspase3. Curcumin at dose of
200 mg/kg was administrated for 4 weeks orally. It decreased aflatoxin
toxicity in kidney via reduction of serum urea, creatinine, uric acid,
MDA and increasing of GSH, total protein levels. Curcumin also de-
creased histopathological changes, pro-apoptotic proteins and pro-in-
flammatory gen such as COX2 [29] (Table 1).
3.1.2. Hepatoprotective
Aflatoxin B1 is common mycotoxin which produced by Aspergillus
flavus and A. parasiticus [30]. AFB1 causes mutagenicity, genotoxicity,
immunosuppression and hepatocellular carcinoma (HCC) in humans
and animals [31,32]. AFB1 is bioactivated by the cytochrome P450 and
produced the AFB1-exo-8, 9-epoxide which lead to reactive oxygen
species (ROS) generation [33]. Curcumin at doses of 100 or 200 mg/kg
decreased ALT, AST, uric acid, creatinine and urea levels [34] (Table 2).
3.2. Lipopolysaccharide (LPS)
3.2.1. Cardioprotective
LPS induces the secretion of inflammatory mediators such as TNF-α,
IL-6, synthesis of nitric oxide and cyclooxygenase 2 [35]. Also, it plays a
role in diseases including neurodegenerative, acute respiratory distress
syndrome, vascular diseases and periodontal diseases [36]. The LPS
toxicity is related to ROS production and the formation of PGE2 and NO
[37]. Also LPS leads to cardiac hypertrophy via increasing of histone
acetylation in myocardium. Histones play a role in response to stress
stimulation in cardiac toxicity [38]. Also p300-HAT is responsible for
LPS-induced cardiac hypertrophy. Curcumin (100 μg/kg) reduced LPS
toxicity in cardiac tissues via remodeling of chromatin, especially his-
tone acetylation and inhibition of p300 p300-HAT activity [39].
3.2.2. Lung protective
LPS plays a role in the pathogenesis of recurrent airway obstruction
which is inflammation problem in horses [40]. LPS is used for in-
flammatory induction in experimental models. It increases the counts of
LPS neutrophil, IL-6, TNF-α, myeloperoxidase and elastase. A lysine salt
of curcumin with name NDS27 reduced LPS-induced inflammation via
decreasing of IL-6, TNF-α, myeloperoxidase and elastase. The observed
effects of curcumin are related to antioxidant activity [41].
3.2.3. Neuroprotective
3.2.3.1. Nitropropionic acid (3-NPA). 3-nitropropionic acid as a toxic
agent is produced by fungi. It is toxic for humans and lead to
disturbance of mitochondrial function. The signs of Huntington's
disease are appeared with this agent [42]. 3-NPA altered the level of
MDA, nitrite (NO2), GSH and neuroinflammatory factors. Curcumin at
doses of 25 and 50 mg/kg improved the signs of toxicity with 3-NPA via
Table 1
Nephroprotective effects of C. longa and curcumin against chemical or natural toxins.
Results Constituents In vitro/In
vivo
Toxin References
Extract decreased Cr, BUN, uric acid and necrosis of kidney C. longa mice Acetaminophen [47]
The level of CYP2E1, iNOSgene IL-1β and TNF-α decreased. The Antioxidant enzymes
increased
Curcumin rats Acetaminophen [49]
Reduced serum urea, creatinine and lipid peroxidation Curcumin and curcumin
nanoparticles
rats Cisplatin [56]
Curcumin increased the levels of NAMPT and SIRT proteins, decreased serum urea, MDA
and kidney injury
Curcumin rats Cisplatin [57]
Decreased MDA, serum urea and creatinine while increment of GSH, SOD and total protein C. onga rats Acrylamid [61]
Reduced urea, cr, uric acid, pro-apoptotic and pro-inflammatory gens. Increased
antioxidant content
Curcumin rats Aflatoxin [29]
Reduced BUN, urea, Cr and MDA Curcumin rats Sodium fluoride [66]
Decreased urea, Cr, lipid peroxidation. Increased the expression of Nrf2/HO-1 and Sirt1 Curcumin rats Gentamicin [71–73]
Decreased MDA, elevated GSH,SOD and CAT Curcumin rats Cadmium [77]
Creatinin (Cr), Blood Urea Nitrogen (BUN), Catalase (CAT), Malondialdehyde (MDA), Super Oxide Dismutase (SOD), Glutathion (GSH), nuclear factor erythroid 2–related factor 2 (Nrf2),
and sirtuin (Sirt).
Table 2
Hepatoprotective effects of C. longa and curcumin against chemical or natural toxins.
Toxin In vitro/In
vivo
Constituents Results References
CCl4 rats C.longa Elevated the level of nuclear translocated Nrf2, reduced AST, ALT and MDA [79,80]
Aflatoxin B1 rats Curcumin nanoparticle Decreased AST, ALT and MDA [34]
Thioacetamide rats C. longa Decreased MDA, nitrotyrosine, urinary 8-OH-dG, TGF-β and TNF-α. Increased
antioxidant enzymes
[83]
Lead acetate rats C. longa Decreased liver enzymes and increased antioxidant content [90]
Lead acetate mice Curcumin or nanocurcumin Decreased liver enzymes and increased antioxidant content [91]
Cadmium rats C. longa Reduced HSC activity, liver fibrosis and hepatic enzymes [94]
Cadmium rats Curcumin Increased antioxidants, scavenge of ROS [95]
Mercury rats Curcumin Changed metallothionein mRNA, increased antioxidant content and chelated mercury [178]
Arsenic rats Curcumin Scavenging free radicals, chelating arsenicals compounds, reduction of lipid peroxidation [102]
Propanil rats Curcumin Reduction of ROS, lipid peroxidation and hepatic enzymes [104]
Cisplatin rats Curcumin Improved hepatic enzymes, liver histopathology, NADPH expression [106]
Nicotine mice Curcumin Reduction of oxidative stress and inflammatory cytokines such as TNF-a and IL-1,
increased liver weight
[111]
Chromium rats Curcumin Improved hepatic structural, enzymes and antioxidant content [119]
Copper rats Curcumin Reduced lipid peroxidation, restored the GSH and antioxidant enzyme levels [122]
Diazinon rats Combination of curcumin and vitamin
E
Elevation of catalase, glutathione peroxidase and glutathione-S-transferase [129]
Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Reactive Oxygen Species (ROS).
A. Hosseini, H. Hosseinzadeh Biomedicine & Pharmacotherapy 99 (2018) 411–421
412

3. increasing of GSH and decreasing of ROS, MDA and NO2 levels [42].
3.2.3.2. D-galactosamine. D-Galactose induces aging processes in animal
models via damage to hippocampal neurons, mitochondrial
dysfunction, and decreasing in protein content [43]. Curcumin at
doses of 50 and 100 mg/kg decreased galactosamine-induced
neurotoxicity via reduction of lipidperoxidation, protein oxidation,
inhibition of caspase3 expression and increasing of antioxidant
content in hippocampus [44] (Fig. 2).
4. Chemical-induced toxicity
4.1. Nephroprotective
4.1.1. Acetaminophen
Acetaminophen is used as analgesic and antipyretic medicine. The
overdose of acetaminophen causes renal toxicity in about 1–2% of pa-
tients. The poisoning of acetaminophen in renal is related to dysfunc-
tion of oxidase isoenzymes which are found in the kidney. Also other
mechanisms play roles in toxicity such as prostaglandin synthetase and
N-deacetylase enzymes. Glutathione has an important role in the neu-
tralization of acetaminophen toxicity [45]. Acetaminophen causes in-
creasing of creatinine, urea and BUN levels as well as the elevation of
proinflammatory cytokines such as TNF-α and IL-1β in the kidney tis-
sues. It increased MDA and NO while decreased GSH level, SOD and
GPx activities. The extract of C. longa (400, 800 and 1000 mg/kg)
showed nephroprotective effects against acetaminophen via decreasing
creatinine, BUN and uric acid levels while acetaminophen elevated
these indexes. Probably, the protective effect of extract is related to
binding to acetaminophen metabolites and decreasing of their affinity
to cellular GSH. Therefore, C. longa elevated the level of GSH and led to
increase in the excretion of acetaminophen metabolites [46,47]. Cur-
cumin at dose of 100 mg/kg reduced nephrotoxicity following acet-
aminophen treatment and improved oxidant/antioxidant imbalance.
The protective effect of curcumin may be due to anti-inflammatory,
antioxidant properties and scavenging of ROS. Also curcumin decreased
NO production via reducing of iNOS expression. Down-regulation of
iNOS led to decreasing of TNF-α and IL-1β formation [48]. This me-
chanism is related to anti-oxidant activity of curcumin [49] (Table 1).
4.1.2. Cisplatin
Cisplatin as chemotherapeutic drug is applied for treatment of dif-
ferent tumors. The important side effect is nephrotoxicity and led to
morbidity and mortality among patients. The toxicity mechanism of
cisplatin is due to inflammation and oxidative stress [50]. Also the le-
vels of tumor necrosis factor-alpha (TNF-α) [51], peroxynitrite anions
[52], superoxide anions [53], hydrogen peroxide [54], and hydroxyl
radicals increased following cisplatin consumption [55]. Cisplatin re-
duces the proteins such as nicotinamide phosphoribosyltransferase
(NAMPT) and sirtuin (SIRT), which interfere in resistance to stress. Also
cisplatin disturbs renal function and elevates urea and creatinine levels
in serum. Curcumin and curcumin nanoparticles reduced cisplatin
toxicity at doses of 30 and 60 mg/kg. These compounds reduced serum
urea, creatinine levels and lipid peroxidation. Curcumin has protective
effects against cisplatin via anti-oxidant function [56]. Also in another
study curcumin at dose of 100 mg/kg decreased kidney injury via de-
creasing of MDA, serum urea and creatinine levels in rats following
cisplatin injection. Also curcumin increased the levels of NAMPT and
SIRT proteins in rats treated with cisplatin [57] (Table 1).
4.1.3. Acrylamide
Acrylamide is a polymer and uses in industry [58]. Also it is pro-
duced when foods are cooked at high temperatures. It leads to toxicity
in different organs such as kidney. Acrylamide is metabolized and
generated reactive oxygen species which leads to oxidative stress, lipid
peroxidation and DNA damages. Recent studies have reported that
herbal medicines which involve in decreasing of acrylamide neuro-
toxicity. Mehri et al. showed thymoquinone [59] and linalool [60] have
neuroprotective effects against acrylamide. C. longa (0.5%) was added
to standard diet. It decreased MDA, serum urea and creatinine levels,
while it increased GSH, SOD and total protein levels in rats that re-
ceived acrylamide [61] (Table 1).
4.1.4. Sodium fluoride
Fluoride is an industrial agent and utilized in dental preparations,
water sources and food preparations [62]. Fluoride enters to blood as
ion via gastrointestinal and lung pathways. The consumption of fluoride
causes systemic problems such as renal injury [63]. Fluoride leads to
changes in renal including inflammation, fibrosis, tubular destruction
and medullar hyperemia [64]. The production of free radicals play a
role in fluoride toxicity [64,65]. Curcumin, at doses of 10 and 20 mg/
kg, reduced fluoride-toxicity in kidney by normalization of blood urea
nitrogen, creatinine, and urea levels. Also curcumin increased anti-
oxidant enzymes and decreased lipid peroxidation [66] (Table 1).
4.1.5. Gentamicin
Gentamicin as an antibiotic is used for treatment of bacterial in-
fection which is caused by gram negative bacteria. Gentamicin induces
nephrotoxicity in 30% of patients who received drug for more than 7
days [67]. The signs of renal dysfunction are as increasing of BUN level
and reducing of glomerular filtration rate [68]. The mechanism of ne-
phrotoxicity is related to production of free radicals such as superoxide
anions, hydroxyl radicals, hydrogen peroxide and reactive nitrogen
species in the kidney [69,70]. The structure of kidney is changed as
degeneration of epithelial lining, disruption of brush borders, disrupted
Bowman's capsule and thickening of afferent arteriole. Also, urea,
creatinine, and uric acid levels were elevated in serum. Administration
of curcumin (200 mg/kg), with rosemary (220 mg/kg), and propolis
(100 mg/kg), ameliorated structural changes and declined urea, crea-
tinine and uric acid levels [71]. Another study showed curcumin
(200 mg/kg) increased the level of catalase, GSH, SOD and GPX activ-
ities while decreased lipid peroxidation [72]. Curcumin (100 mg/kg)
increased Nrf2/HO-1 and Sirt1expression while decreased oxidative
stress [73] (Table 1).
4.1.6. Cadmium
Cadmium (Cd) belongs to heavy metals. It induces toxicity in hu-
mans and animals. Chronic exposure to Cd causes nephrotoxicity [74]
and skeletal damage [75] via production of reactive oxygen species
which causes oxidative stress and lipid peroxidation [74]. In addition,
the level of antioxidant enzymes such as SOD, CAT and GSH reduced in
Cd toxicity [76]. Moreover, structural modifications were observed in
renal tissues. Curcumin, at dose of 250 mg/kg, declined histological and
biochemical changes. It decreased MDA level, elevated GSH level and
improved proximal tubular changes [77] (Table 1).
4.2. Hepatoprotective activity
4.2.1. Carbon tetrachloride (CCl4)
Carbon tetrachloride (CCl4) is a toxic agent for liver and uses in
experimental models for induction of hepatotoxicity. A single dose of
CCl4 causes liver problems via generation of ROS [14]. CCl4 is meta-
bolized and produced free radicals such as trichloromethyl (CCl3%) and/
or trichloromethyl peroxyl (CCl3OO%). These free radicals attack to
cellular molecules and lead to apoptosis and necrosis [78]. Adminis-
tration of C. longa (50 or 100 mg/kg) in CCl4-treated rats decreased
serum AST, ALT and MDA levels. The activity of antioxidant enzymes,
such as catalase, superoxide dismutase, and glutathione peroxidase
increased. Also the extract elevated the level of nuclear translocated
Nrf2. Increasing of Nrf2 led to activation of the antioxidant and phase II
detoxifying enzymes such as glutathione S-transferase. Therefore, C.
longa has protective effects against CCl4 via increasing of antioxidant
A. Hosseini, H. Hosseinzadeh Biomedicine & Pharmacotherapy 99 (2018) 411–421
413

4. enzymes and activation of nuclear translocated Nrf2 [79,80] (Table 2).
4.2.2. Thioacetamide
Thioacetamide is a hepatotoxic agent and causes liver disorders in
experimental models [81]. Hepatic microsomal cytochrome P4502E
converts thioacetamide to TAA-S -oxide (TASO) and then to toxic
thioacetamide S-dioxide (TASO2) which TASO2 leads to liver cirrhosis.
Thioacetamide elevates the level of liver enzymes such as ALP, ALT,
AST and bilirubin [82]. C. longa extract at doses of 250 and 500 mg/kg
reduced the liver enzymes, MDA, nitrotyrosine, and urinary 8-OH-dG
levels. The extract increased antioxidant enzymes such as SOD and
catalase and reduced inflammatory factors such as TGF-β and TNF-α.
However, C. longa reduced the progression of liver cirrhosis via anti-
oxidant and anti-inflammatory activities [83] (Table 2).
4.2.3. Lead acetate
Lead is belonging to heavy metals and causes pollution in en-
vironment. Also it is danger for animals and humans [84]. The me-
chanism of toxicity is via oxidative stress and production of ROS [85]. It
reduces CYP450 content in liver [86], inhibits synthesis of heme [87],
suppresses antioxidant enzymes [88] and declines GSH [89] and in-
creases ALT, AST and ALP levels. The studies have shown C. longa at
dose of 500 mg/kg [90] and curcumin or nano-curcumin (15mg/kg)
protected liver against lead acetate via reducing oxidative stress, liver
enzymes and lipid-peroxidation while increased antioxidant content
such as SOD [91] (Table 2).
4.2.4. Cadmium
Cadmium damages to liver via increasing of hepatic enzymes such
as ALP, AST, ALT and activating of hepatic stellate cells (HSC) into
myofibroblast-like cells which are responsible liver fibrosis [92,93].
Administration of C. longa decreased the activation of HSC cells, liver
fibrosis and hepatic enzymes [94]. Also curcumin at doses of 200 and
400 mg/kg in combination with vitamin C reduced cadmium-induced
hepatotoxicity via scavenging ROS, increasing of GSH level and other
antioxidant enzymes [95] (Table 2).
4.2.5. Mercury
Mercury causes the production of HO_, H2O2 and ROO_. These
compounds attach to membrane of cells and lead to cell death, reduc-
tion of SOD, CAT, GSH, sulfhydryl groups of proteins and GPx (Şener
et al., 2007; Pal and Ghosh, 2012). Curcumin at dose of 80 mg/kg in-
creased antioxidant enzymes, chelated mercury in tissue, reduced the
concentration of mercury and changed the expression of metallothio-
nein mRNA [95] (Table 2).
4.2.6. Arsenic
Humans or animals are exposed to arsenic via war [96], environ-
ment or drugs [97]. Arsenic causes liver diseases such as hepatomegaly,
hepatoportal sclerosis, ascites, liver fibrosis and cirrhosis [98,99]. In-
flammation, oxidative stress, apoptosis [100], necrosis, NADPH oxidase
and TGF-b/SMAD activation [101] play roles in pathogenesis of arsenic
hepatotoxicity. Curcumin at dose of 15 mg/kg reduced arsenic-induced
liver damage via reduction of lipid peroxidation, increasing of GSH
content, elevation of antioxidant enzymes such as GST, SOD, CAT and
prevention of thiol depletion. Thus, curcumin protects arsenic-induced
hepatic damage via scavenging free radicals and chelating arsenicals
compounds [102] (Table 2).
4.2.7. Propanil
Propanil is an herbicide and has been used in agriculture industry.
Whereas, this agent is applied for rice and wheat crops, however poi-
soning of humans with this compound is high. Exposure to propanil
causes toxicity in humans and animals. Recent studies have shown that
exposure of mice with propanil induced histopathological changes in
liver [103]. Curcumin at dose of 50 mg/kg attenuated propanil toxicity
via reduction of lipid peroxidation, hepatic enzymes and increasing of
antioxidant enzymes [104] (Table 2).
4.2.8. Cisplatin
Cisplatin is chemotherapeutic drug and causes different side effects
such as hepatotoxicity. The cisplatin mechanism for liver injury is re-
lated to oxidative stress and generation of ROS which damage to cell
membrane [105,106]. The balance between oxidant and antioxidant is
disturbed [107]. Cisplatin increased MDA while declined SOD and
catalase. It increased the level of hepatic enzymes such as ALT and AST.
Also the expression of NADPH oxidase gene increased in the presence of
cisplatin. Curcumin at dose of 200 mg/kg improved the liver enzymes,
lipid peroxidation biomarker, liver histopathology and gene expression
of liver NADPH oxidase [106] (Table 2).
4.2.9. Nicotine
Nicotine is found in cigarette and tobacco [108]. Exposure to ni-
cotine causes oxidative injury, depletion of glutathione, reducing of free
radical scavengers such as CAT and SOD [109].The liver is a target for
nicotine toxicity [110]. Liver weight reduced by nicotine while dia-
meter of hepatocytes, and hepatic enzymes increased. Also nicotine
damages to cell membrane of hepatocytes. Also it leads to necrosis and
releasing of hepatic enzymes into blood. The study had shown curcumin
(10, 30 and 60 mg/kg) decreased hepatotoxicity of nicotine via reduc-
tion of oxidative stress and inhibition of TNF-α and IL-1 secretion.
Curcumin increased liver weight, improved hepatocyte diameter, cen-
tral hepatic vein, hepatic enzymes and nitric oxide [111] (Table 2). Also
curcumin reduced carcinogenic effect of tobacco in liver via inter-
ference with Mitogen-activated protein kinase (MAPK) pathway [112].
4.2.10. Chromium
Different studies have shown which chromium causes hepatotoxi-
city as the parenchym necrosis and steatosis of hepatocytes [113].
Chromium hepatotoxicity is accompanied with elevation of ROS levels
[114], damage to DNA, lipid peroxidation, disturbance in synthesis of
DNA, RNA and protein [115], mitochondrial destruction [116], cell
growth inhibition [117] and apoptosis [118]. The combination of cur-
cumin (400 mg/kg) with potassium dichromate (15 mg/kg) reduced
chromium-induced liver injury via decreasing of hepatocyte damage,
histopathological changes and improving of antioxidant enzymes such
as SOD, CAT, GPx, GR and GST [119] (Table 2).
4.2.11. Copper
The food is containing of copper which enters to hepatocytes via
portal vein. The accumulation of copper in liver lead to hepatic failure,
necrosis, cholestasis, cirrhosis and finally death [120]. The mechanisms
of hepatocyte toxicity are involving ROS production, oxidation of GSH,
lipid peroxidation and mitochondrial dysfunction [121]. Curcumin re-
duced lipid peroxidation, expression of some cytokines such as TNF-α
and IL-8, restored the antioxidant enzyme levels, and prevention of
apoptosis. Also it ameliorated histopathological changes [122]
(Table 2).
4.2.12. Diazinon
Diazinon belongs to organophosphate agents and uses in agriculture
for controlling of insects in crops. It causes toxicity via prevention of
acetyl cholinesterase activity. Also it changes mitochondrial membrane
in liver of rat [123] and leads to disturbance of cytochrome P450 in
human liver [124]. Diazinon causes oxidative stress, increases lipid
peroxidation and free radical [125]. However, antioxidant compounds
can reduce the toxicity of diazinon in liver and other tissues [126–128].
Curcumin at dose of 50 mg/kg in combination with vitamin E increased
catalase, glutathione peroxidase and glutathione-S-transferase. It de-
creased aspartate transaminase, alanine transaminase, lactate dehy-
drogenase and alkaline phosphatase in rats which received diazinon
[129] (Table 2).
A. Hosseini, H. Hosseinzadeh Biomedicine & Pharmacotherapy 99 (2018) 411–421
414

5. 4.3. Cardioprotective activity
4.3.1. Streptozotocin
Streptomycetes synthesizes streptozotocin (STZ) which can lead to
diabetes mellitus in animal models [130]. One of diabetic problems is
heart failure. The studies have reported that curcumin has protective
effects against STZ-induced diabetes and heart failure in rats. STZ in-
creases glucose, triglycerides, cholesterol (TC), nitric oxide, lactate
dehydrogenase, the level of MDA in cardiac, IL-6 and TNF-α in plasma.
Also STZ reduces the level of antioxidant enzymes in cardiac. Curcumin
showed protective effects against STZ-induced heart failure via anti-
oxidant activity and anti-inflammatory. It increased the level of GSH,
SOD and CAT in heart [131] (Fig. 1).
4.3.2. Doxorubicin
Doxorubicin as chemotherapeutic agent is used in cancer patients.
The important side effect is cardiotoxicity which lead to restriction of
consumption. Curcumin at dose of 100 mg/kg reduced cardiotoxicity
effects of doxorubicin. Curcumin at dose of 200 mg/kg declined mor-
tality, improved body weight, decreased oxidative stress, increased
anti-oxidant enzymes via scavenging of free radicals and anti-in-
flammatory effects [132].
C. longa as ethanolic or water extract at dose of 200 mg/kg reduced
mortality following doxorubicin administration. Also the extract de-
creased activity of CK-MB activity, the levels of LDH, and MDA and
increased GSH level. Moreover, the extract reduced nitric oxide and
increased ascorbic acid concentration in cardiac tissue, and improved
the activities of antioxidant enzymes [133] (Fig. 1).
4.3.3. Cyclosporin A
Cyclosporin A is used in autoimmune disease and for avoiding graft
rejection but it causes adverse effects such as cardiotoxicity and hy-
pertension. Cyclosporin A leads to disturbance of aortic endothelial
function via change in morphology and structure in tissue, elevation of
MDA and NO levels in endothelial. Curcumin (200 mg/kg) decreased
the cardiotoxicity effect of cyclosporin A via anti-oxidant activity and
improved cardiac dysfunction [134] (Fig. 1).
4.3.4. Methotrexate
Methotrexate (MTX), an antifolate drug, is used in rheumatoid ar-
thritis, psoriasis and cancer diseases. It causes oxidative stress and leads
to endothelial injury. The protective effects of curcumin on MTX in-
duced vascular endothelial dysfunction have been observed. Curcumin
at doses of 200 and 400 mg/kg prevented vascular side effects by de-
creasing oxidative stress and nitric oxide levels [134] (Fig. 1).
4.3.5. Isoproterenol
Isoproterenol (isoprenaline) as non-selective β agonist is used for
treatment of asthma, bradycardia and heart block. The studies have
shown that isoprenaline causes cardiotoxicity in rats [135]. It increased
LDH, creatine kinase (CPK), AST, ALT and lipid peroxidation. Also it
reduced antioxidants enzymes such as SOD, CAT, and tissue GSH levels.
Curcumin at doses of 200 mg/kg improved these changes and showed a
protective effect against isoproterenol-induced cardio toxicity by
Fig. 1. Protective effect of C. longa or curcumin against chemical-in-
duced cardiotoxicity.
C. longa and natural toxins: C.longa and curcumin as its active com-
pound reduced apoptosis and inflammation in cardiac tissues via in-
creasing of antioxidant agents (SOD, GSH, CAT), decreasing of cyto-
kines (IL-6, TNF-α, iNOS), apoptotic proteins (Bax, bcl2, caspase3)
and oxidative stress (MDA, ROS).
Reactive Oxygen Species (ROS), Malondialdehyde (MDA), Lactate
dehydrogenase (LDH), Creatinine PhosphoKinase (CPK).
Fig. 2. Protective effect of C. longa or curcumin against chemical-in-
duced neurotoxicity.
C. longa and neuroprotection against chemical toxins: C.longa and
curcumin decline neurodegeneration by scavenging of free radicals,
decreasing of inflammatory pathway and restore of anti-oxidant en-
zymes.
Malondialdehyde (MDA), Reactive Oxygen Species (ROS), Super
Oxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT),
Cyclooxygenase2 (COX2.
A. Hosseini, H. Hosseinzadeh Biomedicine & Pharmacotherapy 99 (2018) 411–421
415

6. antioxidant defense [136] (Fig. 1).
4.3.6. Cadmium
Cadmium as a heavy metal causes environmental pollution.
Different sources are responsible for air pollution by cadmium such as
burning of fossil, phosphate fertilizers, production of iron and steel, and
other activities [137]. Humans are contaminated with cadmium via
different routes including lung and gastrointestinal tract [137]. Oxi-
dative stress plays a role in cadmium-induced toxicity in different tissue
via damage to vascular and hypertension [137]. The protective effect of
curcumin against cadmium toxicity has been reported. Curcumin at
doses of 50 or 100 mg/kg normalized vascular dysfunction and blood
pressure following cadmium toxicity. The protective mechanism of
curcumin is related to generation of endothelial nitric oxide synthase
(eNOS) protein, elevation of GSH redox ratio and reduction of super-
oxide (O2−) production in vascular smooth muscle. Antioxidant ac-
tivity and chelating properties play a role in protective effects of cur-
cumin against cadmium [138] (Fig. 1).
4.3.7. Diesel exhaust particles (DEP)
Diesel exhaust particles lead to cardiopulmonary problems. Also,
exposure to this agent causes inflammation of lung and peripheral
thrombotic events. DEP lead to elevation of plasma C-reactive protein
(CRP), TNF-α, plasminogen activator inhibitor-1 (PAI-1) levels and
systolic blood pressure (SBP). Curcumin reduced cardiotoxicity via anti-
inflammatory effects. Also it decreased the levels of CRP and TNFα as
well as PAI-1 activity [139] (Fig. 1).
4.3.8. Nicotine
Nicotine is present in cigarette and tobacco. It involves in patho-
genesis of cardiovascular disease and lung cancer. Curcumin at dose of
80 mg/kg has a protective effect against nicotine via reduction of AST,
ALT, ALP and LDH [140] (Fig. 1).
4.3.9. Cyclophosphamide
Cyclophosphamide as an alkylating agent is applied in suppression
of immune system and cancer. Its metabolites bind to DNA and pro-
teins. The most important adverse effect of this anticancer agent is
cardiac injury which is observed as CHF, arrhythmias, cardiac tampo-
nade, and myocardial depression. Cyclophosphamide induces cardio-
toxicity via free radical generation and decreasing of antioxidant en-
zymes in heart tissue. In addition, cyclophosphamide causes
hypertriglyceridemia, hypercholesterolemia, and disturbs the secretion
of cardiac lipoprotein lipase [141]. Also it elevated the levels of LDH,
CK-MB, CK-NAC, AST, ALT, and ALP while curcumin reduced these
indexes in cardiac tissues. Also cyclophosphamide changed ECG para-
meters such as a reduction in heart rate and RR interval and pro-
longation of QT, PR and QRS intervals. Curcumin restored these para-
meters and prevented cardiac damage by reducing the inflammation
and fragmentation of myofibrils [142] (Fig. 1).
4.4. Neuroprotective activity
4.4.1. Cisplatin & oxaliplatin
Cisplatin and oxaliplatin are commonly used in treatment of cancer.
These drugs cause peripheral neuropathy and neuropathic pain.
Oxidative stress is responsible for neurotoxicity of these drugs.
Curcumin at dose of 10 mg/kg reversed the alterations of neuro-
tensin in the plasma and ameliorated sciatic nerve histology in rats
[143] (Fig. 2).
4.4.2. Haloperidol
Tardive dyskinesia is a motor disorder which is commonly appeared
with antipsychotic drugs such as haloperidol. Haloperidol increases of
vacuous chewing movements (VCM's), tongue protrusions, facial
jerking in rats which are reduced by curcumin. Oxidative stress plays a
role in neurotoxicity and tardive dyskinesia of haloperidol [144], thus
curcumin at dose of 50 mg/kg reduced the signs of tardive dyskinesia
via anti-oxidant activity [145] (Fig. 2).
4.4.3. Mono sodium glutamate (MSG)
Mono sodium glutamate as a flavor enhancer causes neuronal signs
such as weakness, dizziness and headache. MSG changes lipid perox-
idation and antioxidant activity of enzymes in cerebral brain and other
related regions [146]. Also behavioral abnormalities are observed with
MSG [147]. Curcumin (150 mg/kg) declined acetyl choline esterase
(AchE) activity and inflammation in neurons, thus protected neurons
against MSG. Also curcumin reduced glutamate level and gene ex-
pression of receptors including NMDA2B and mGLUR5 in brain hip-
pocampus [148] (Fig. 2).
4.4.4. Aluminium
Aluminum as a heavy metal is found in food products and water.
Aluminium induces neurotoxicity and is accompanied with Alzheimer’s
disease (AD). Aluminium prompts oxidative stress and elevates the level
of amyloid beta in in vivo. Chronic exposure to aluminium increases
lipid peroxidation, nitrite levels, reduces glutathione levels, catalase,
superoxide dismutase and glutathione-S-transferase activity. Also, it
leads to elevation of acetylcholinesterase activity. Curcumin (30 mg/
kg) reduced aluminium toxicity via memory improvement, decreased
acetylcholinesterase activity, oxidative damage and aluminium con-
centration. Thus, curcumin showed a neuroprotective effect against
aluminium toxicity [149,150] (Fig. 2).
4.4.5. Cadmium
Some studies have shown cadmium is a toxic agent and exposure to
this agent causes loss of weight, behavioral problems and neuronal
dysfunction [151]. Also cadmium changes neurotransmitters and anti-
oxidant enzymes in brain. Curcumin at dose 300 mg/kg ameliorated
cadmium-induced toxicity in brain. It improved memory, learning,
behavioral problems and biochemical alterations [152] (Fig. 2).
4.4.6. Fluoride
Fluoride, as an inorganic ion, leads to various problems including
neurological dysfunction. Fluoride causes oxidative stress in brain via
penetration and accumulation [153]. Curcumin at dose of 30 mg/kg
declined fluoride neurotoxicity by antioxidant activity which lead to
oxidative stress reduction and decreasing of neurodegeneration [154]
(Fig. 2).
4.4.7. Formaldehyde (FA)
Formaldehyde as an aldehyde compound causes toxicity in human
and animals. FA increases ROS production and damages to DNA.
Curcumin at dose of 100 mg/kg decreased FA-induced neurotoxicity via
antioxidant activity [155] (Fig. 2).
4.4.8. Rotenone
Rotenone as pesticide has toxicity for humans and other animals.
The signs of toxicity with rotenone appear as Parkinson. Oxidative
stress involves in pathogenesis of Parkinson. Curcumin at dose of
100 mg/kg has a neuroprotective effect against rotenone toxicity [156].
Curcumin improved tyrosine hydroxylase (TH) and motor dysfunction
in rats which received rotenone. Moreover, curcumin decreased the
production of ROS and MDA while increased glutathione content. Act/
Nrf2 pathway plays role in reduction of rotenone-induced neurotoxicity
by curcumin [156] (Fig. 2).
4.4.9. Vincristine
Vincristine is an anticancer. This drug leads to neuropathy and in-
flammation in neuron tissues [157]. Curcumin at doses of 40 and
80 mg/kg attenuated vincristine neurotoxicity via increasing of GSH,
catalase, glutathione peroxidase and SOD. The neuroprotective effects
A. Hosseini, H. Hosseinzadeh Biomedicine & Pharmacotherapy 99 (2018) 411–421
416

7. of curcumin may be related to anti-inflammatory, anti-nociceptive,
antioxidant and calcium inhibitory effects [158]. Curcumin decreased
lipid peroxidation, nitric oxide and TNF-α level while elevated anti-
oxidant levels such as GSH, SOD, CAT and GPx (Fig. 2).
4.4.10. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
MPTP is converted to MPP + which is a neurotoxin agent in dopa-
minergic neurons and causes Parkinson via oxidative stress [159]. CNB-
001 (24 mg/kg) is derived from curcumin and has therapeutic effects
against MPTP-induced Parkinson via decreasing of oxidative stress,
reduction of dopamine transporter and tyrosine hydroxylase expression
[160] (Fig. 2).
4.4.11. Pentylenetetrazole (PTZ)
PTZ is used for induction of seizure in experimental animals [161].
Curcumin at doses of 100 mg/kg and 300 mg/kg prevented PTZ effects
via reducing oxidative stress, improvement of mitochondrial function
and memory in rats [162] (Fig. 2).
4.4.12. Sevoflurane (SEVO)
SEVO is used as inhalational anesthetic agent but it causes neuro-
logical problem in the brain and damages to neurons. Curcumin re-
duced the side effects of sevoflurane via reducing of oxidative stress,
inflammation, apoptosis and improvement of cognitive function [163]
(Fig. 2).
4.4.13. Acrylamide (ACR)
ACR is used in preparation of dyes, paper and plastic. Also it is
produced in food when the temperature is high. ACR is absorbed from
skin easily and entered to organs [164]. It is especially toxic for neurons
and some studies have reported the protective effects of herbal medi-
cines such as crocin in in vivo [165] and in vitro against ACR [166].
Curcumin at dose of 50 mg/kg ameliorated ACR-induced neurotoxicity
via reduction of oxidative stress. It elevated antioxidant content and
improved mitochondrial function. Also the activity of acet-
ylcholinesterase is restored to normal level in rats which received
curcumin. However, curcumin decreased ACR-toxicity via reduction of
oxidative stress, amelioration of acetylcholinesterase activity and de-
creasing function of cytosolic calcium [167] (Fig. 2).
4.4.14. Streptozotocin (STZ)
Streptozotocin is used for induction of Alzheimer's disease in animal
models. The studies have shown that curcumin has a protective effect
against STZ-induced neurotoxicity via reducing of oxidative stress and
apoptosis. Also it decreased the storage of β-amyloid in the brain and
led to improvement of cognitive problems [168] (Fig. 2).
4.4.15. Arsenic
Arsenic is belonging to heavy metals. It is toxic for different tissues
such as brain [169]. Curcumin and nanoparticle of curcumin have
protective effects against arsenic toxicity. They decreased lipid perox-
idation and ROS production while increased antioxidant content in the
brain [170] (Fig. 2).
4.4.16. Oxaliplatin
Oxaliplatin is applied for treatment of metastatic colorectal cancer.
The use of this drug is limited because of neurotoxicity via oxidative
stress [171]. Curcumin reduced toxicity by inhibition of oxidative stress
and elevation of antioxidant enzymes [171] (Fig. 2).
4.5. Lung protective
4.5.1. Chlorpyrifos
Chlorpyrifos is used in agriculture industry. Chlorpyrifos causes
different side effects including genotoxicity, teratogenicity, hematolo-
gical and immunological abnormalities, neurotoxicity, and hepatic
dysfunction [172]. Chlorpyrifos leads to toxicity in lung via production
of free radicals, lipidperoxidation and reduction of antioxidant en-
zymes. Curcumin at doses of 100 and 300 mg/kg in combination with
vitamin E decreased these changes via scavenging of ROS and elevation
of antioxidant enzymes [173].
4.5.2. Paraquat
Paraquat damages to lung and leads to pulmonary fibrosis via
production of free radicals, releasing of inflammatory factors and pro-
teolytic enzymes. Paraquat at dose of 50 mg/kg increases alkaline
phosphatase, angiotensin converting enzyme and N-acetyl-beta-D-glu-
cosaminidase. Also it elevates MDA, neutrophils and decreases glu-
tathione. Curcumin reduced the toxicity via anti-inflammatory and
antioxidant activities [174].
4.6. Genoprotective
4.6.1. Chromium trioxide
Chromium belongs to heavy metals and is widely used by human in
different industries. Also there is in air as Cr (III) and Cr (VI) which Cr
(VI) is more toxic because of it converts to Cr (III) that crosses cell
membrane and binds to macromolecules. It damages to DNA via free
radical production and causes genotoxicity. The studies have shown
curcumin reduced chromium-induced genotoxicity [175].
4.6.2. Cyclophosphamide
Cyclophosphamide is used as anti-cancer drug. It damages to pro-
tein structure via binding to DNA and RNA. Also it disturbs chromo-
somal structure in different steps of spermatogenesis in germ cells.
Curcumin at doses of 10, 15 and 20 mg/kg reduced the percentage of
abnormal sperms following cyclophosphamide administration in mice.
Therefore, curcumin has protective effects against drugs which induce
genotoxicity [176].
4.6.3. Copper
The studies have shown exposure to high concentration of copper
leads to DNA damage and genotoxicity. The exposure with curcumin)
0.2% (could decrease genotoxicity of copper in mice [177].
5. Conclusion
Nowadays herbal medicines are used in most of diseases because of
different properties such as antioxidant effects. Exposure to chemical
and natural toxins for long term can lead to toxicity in animal or
human. These toxins cause toxicity in different organs including car-
diovascular system, brain, liver, renal and lung. The recent studies have
shown herbal medicines play roles in reduction of toxicity of these
agents. One of herbal medicine which has more pharmacological effects
is C. longa and its active constituent, curcumin. Most of studies have
shown that C. longa and its active compounds reduced nephrotoxicity,
hepatotoxicity, cardiotoxicity, neurotoxicity and lung toxicity mainly
through the reduction of inflammatory cytokines, antioxidant and an-
tiapoptotic effects.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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