Onion (Allium cepa) and its Main Constituents as Antidotes or Protective Agents against Natural or Chemical Toxicities: A Comprehensive Review

Iranian Journal of Pharmaceutical Research (2021), 20 (1): 3-26
DOI: 10.22037/ijpr.2020.112773.13940
Received: November 2019
Accepted: June 2020

 Review Paper

 Onion (Allium cepa) and its Main Constituents as Antidotes
 or Protective Agents against Natural or Chemical Toxicities: A
 Comprehensive Review

 Mahyar Dorrigiva, Armin Zareiyanb* and Hossein Hosseinzadehc, d*

 Department of Pharmacognosy, Faculty of Medicine, AJA University of Medical Sciences,
 a

 Tehran, Iran. bPublic Health Department, Nursing Faculty at Aja University of Medical Sciences,
 Tehran, Iran. cPharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad
 University of Medical Sciences, Mashhad, Iran. dDepartment of Pharmacodynamics and
 Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

 Abstract

 Onion (Allium cepa) is a member of the family Amaryllidaceae and one of the most widely
 cultivated species of the genus Allium. Onion has plentiful chemical compounds such as allicin,
 quercetin, fisetin, other sulphurous compounds: diallyl disulphide and diallyl trisulphide.
 Onion and its main components in specific doses have shown a lot of benefits including free-
 radical scavenging and antioxidant properties, anticholesterolemic, anti-heavy metals toxicity,
 antihyperuricemia, antimicrobial, anti-gastric ulcer, and anticancer. This study summarizes
 numerous in-vitro and animal studies on the protective effects of onion against natural and
 chemical toxicities. Onion and its main components can ameliorate the toxicity of chemical agents
 in kidney, liver, brain, blood, heart, reproductive system, embryo, pancreas through reducing
 lipid peroxidation, antioxidant effect, radical-scavenging, anti-inflammatory, chelating agent,
 cytoprotective activities, increasing protein synthesis in damaged tissues, suppressing apoptosis,
 as well as modulation of PKC- /p38MAPK, Wnt/beta-Catenin, ERK, JNK, p38 MAPK, Bcl-2,
 Bax, and NF-κB signaling pathways.

 Keywords: Onion; Allium cepa; Protective effect; Antidote; Venom; Toxicity; Toxin.

 Introduction antiasthmatic, antithrombotic activity,
 antiplatelet activity, antibiotic effects, and
 Onion (Allium cepa) belonging to the ability to modulate the detoxification systems
family Amaryllidaceae and the genus Allium (7). According to various studies and research
is a notable spice around the world, probably projects, onion has a lot of health benefits,
native from the south-west of Asia. Onion is such as amelioration of renal failure (8-10),
the origin of numerous phytomolecules, such antidiabetic, hypotensive, hypolipidemic
as polyphenolic substances, phenolic acids, properties (11-14), and lowering blood uric
flavonoids (fisetin, quercetin) (1-4), ascorbic acid (15). Additionally, in various studies
acid, and sulphur compounds (5, 6) that are onion and its main components have a variety
responsible for its color, flavor, and aroma as of protective effects in different organs and
well as for its possible health advantages, such tissues including liver (1, 11 and 16), intestine
as its anti-toxic, anticarcinogenic properties, (17), heart (18), testis (12, 19), kidney (9, 13),
* Corresponding authors: blood (20), bone marrow (21) and brain (22,
 E-mail: a.zareian@ajaums.ac.ir; 23). Other herbs and their main ingredients such
 hosseinzadehh@mums.ac.ir as saffron, Vitis vinifera (24), Curcuma longa

Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

(25), Cinnamomum zeylanicum (26), Berberis of onion against natural toxins and chemical-
vulgaris (27), Nigella Sativa (28), green tea induced toxicity. The effects of onion and
(29), and lycopene (30) play important roles as its major components against toxicities of
an antidote or protecting agents against both natural, industrial chemicals, drugs and health
natural and chemical toxicities. This article has care products agents are introduced in Tables
reviewed the antidotal and protective effects 1-3 and Figures 1 and 2.
Table 1. Protective effects of onion and its main constituents against natural agents induced toxicity.

Table 1. Protective effects of onion and its main constituents against natural agents induced toxicity.

 Study design and
 dose of garlic/
 Agent Type of toxicity Type of study Effect demonstrated References
 garlic component
 evaluated

 The protective role of these extracts may
 be due to their rich content of
 Aflatoxin In-vivo, male Ethanolic onion
 Heart, liver, and organosulfur compounds, which act as a
 Sprague-Dawley extract (2 weeks, 5 (31)
 kidney toxicities precursor of GSH, which conjugates with
 rats mg/kg, p.o.)
 aflatoxin-epoxide and results in the
 inhibition of epoxide binding to DNA

 onion oil (45 mg)
 Onion oil reduces Toxin concentration
 Clostridium In-vitro, Meat was dissolved in
 - produced in meat slurry systems by C. (33)
 botulinium slurry miglyol to a final
 botulinum type A, B, and C
 volume of 1.0 mL

 In-vitro, the Vero
 (African green
 Clostridium Fresh onion bulb Fresh onion bulb extracts reduced toxin
 Cell toxicity monkey kidney) (34)
 difficile extract production and activity significantly.
 and HT-29 (human
 colon carcinoma)

 In-vivo, Sprague-
 Onion extract (18 Antioxidative and anti-lipid peroxidative
 Nicotine Lung toxicity Dawley adult male (14)
 weeks, p.o.) mechanisms.
 albino rats

 Restored LPS-suppressed bone
 mineralization and the mRNA and
 protein expression levels of osteoblast-
 Bone marrow In-vitro, MC3T3-
 LPS Quercetin specific genes such as Osterix (OSX), (21)
 toxicity E1 cells,
 runt-related transcription factor 2
 (Runx2), alkaline phosphatase (ALP) and
 osteocalcin (OCN)

 Onion extract takes protective action
 In-vitro, BV-2 against LPS and MPP+, and upregulates
 Methanol extract
 LPS Cell toxicity microglial cells, the antioxidant enzymes that could (41)
 of onion
 N27-A cells potentially be used in the therapy of
 neurodegenerative diseases

 N. n. Ethanolic onion Neutralize snake venom proteins due to
 In-vitro , hen’s egg
 karachiensis Hematotoxicity extract (0.1 to 0.6 the abundance of miscellaneous (35)
 yolk mixture
 toxin mg/mL) secondary metabolites.

 Heart, liver,
 N. n. Ethanolic onion Secondary metabolites pose a hindrance
 kidney, and In-vivo, male
 karachiensis extract (100 in the binding of different snake venom (36)
 musculoskeletal rabbits
 toxin mg/kg, sc) enzymes to their potential targets.
 toxicities

 Secondary metabolites created
 N. n. disturbances in binding of 5í-
 Methanolic onion
 karachiensis Hematotoxicity In-vitro nucleotidases to their receptor(s), (39)
 extract
 toxin therefore resulted in the recovery of
 different toxicities.

 N. n. Ethanolic onion Neutralize snake venom proteins due to
 In-vitro, hen’s egg
 karachiensis Hematotoxicity extract (0.1 to 0.6 the abundance of miscellaneous (37)
 yolk mixture
 toxin mg/mL) secondary metabolites.

 allylsulfide,
 Gastrointestinal By inhibition of gastric secretion
 Histamine In-vivo, rats allyldisulfide and (42)
 toxicity stimulation effect of histamine.
 quercetin

 4

Onion as an Antidote

 Figure 1. Some protective effects of Allium cepa against toxicity with its underlying mechanisms. CAT: Catalase; GSH: Glutathione; SOD:
 Superoxide dismutase; AST: Aspartate Aminotransferase; ALT: Alanine transaminase; MDA: Malondialdehyde; GST: Superoxide Dismutase;
Figure 1. Some protective effects
 SCr: serum creatinine; Allium
 ofLDH: Lactatecepa againstALP:
 dehydrogenase, toxicity
 Alkaline with its underlying mechanisms. CAT: Catalase; GSH: Glutathione; SOD:
 Phosphatase.
Superoxide dismutase; AST: Aspartate Aminotransferase; ALT: Alanine transaminase; MDA: Malondialdehyde; GST: Superoxide Dismutase; SCr:
serum creatinine; LDH: Lactate dehydrogenase, ALP: Alkaline Phosphatase.

Figure 2. Protective
 Figure effects
 2. Protective effects of Alliumcepa
 of Allium cepa
 (A. (A. cepa)
 cepa) extract
 extract againstagainst natural
 natural agents, agents,
 industrial industrial
 agents, agents,
 and drugs andcare
 and health drugs and health care agents.
 agents.

 5

Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

Table 2.
Table 2. Protective
 Protectiveeffects of of
 effects onion andand
 onion its main constituents
 its main against
 constituents industrial
 against chemicals
 industrial induced toxicity.
 chemicals induced toxicity.

 Study design and dose of
 Type of
 Agent Type of study garlic/garlic component Effect demonstrated References
 toxicity
 evaluated
 In-vitro, Bolti
 fish (Tilapia
 Acrylamide Hepatotoxicity Onion peel powder Direct ROS scavenging activity (16)
 nilotica) liver
 cells
 significant reduction in free radical
 In-vivo, male Quercetin (100 mg/kg, 2 concentration and induction of the
 Aluminum neurotoxicity (46)
 albino rats months, p.o.) activity and gene expression of the
 brain antioxidant enzymes

 A. cepa reduced aluminium
 deposition in the brain, which could
 Onion hydroethanolic extract
 In-vitro, Swiss be the major mechanism responsible
 Aluminum neurotoxicity (50, 100 and 200 mg/kg/day, (45)
 albino male mice for its neuroprotective potential
 2 months, p.o.)
 besides inhibiting the ROS
 production

 In-vitro, Adult Liposomal quercetin (2.71
 Hepatotoxicity, Liposomal quercetin reduce arsenic
 Arsenic female Swiss mg /kg BW, twice a week for (48)
 neurotoxicity deposition in the brain and liver
 albino rats 4 months, S.C.)

 hydro-acetone phenolic-rich The extract possesses mainly
 Carbon Nephrotoxicity, extract of red onion peels (50 various phenolic phytochemicals
 In-vitro, rats (49)
 tetrachloride hepatotoxicity and 100 mg/kg/rat, 17 days, which can diminish the free radicals-
 p.o) induced oxidative stress

 Diesel freeze-dried onion powder, effects depend on the aryl
 reproductive In-vivo, BALB/c
 exhaust 0.5% w/w of the daily diet, 5 hydrocarbon receptors antagonistic (4)
 toxicity male mice
 particles weeks, p.o) function

 In-vivo, Male Ameliorate ethanol-induced fatty
 Onion wine extract (1 mL/d,
 Ethanol Hepatotoxicity Sprague-Dawley liver by lowering hepatic and blood (11)
 6 weeks, p.o.)
 rats lipid levels

 Restored the alcohol-induced
 histological alterations, antioxidants
 In-vivo, male Fisetin (5 mg/kg, 8 defenses, NF-κB expression and
 Ethanol Hepatotoxicity (1)
 C57BL/6 mice consecutive days, p.o.) stabilized the matrix
 metalloproteinases (MMPs) activity
 in the liver tissue
 Allyl methyl trisulfide
 (AMT), allyl methyl disulfide
 Gastrointestinal In-vivo, female Induced increased glutathione S-
 Benzopyrene (AMD), diallyl trisulfide (17)
 toxicity A/J mice transferase (GST) activity
 (DAT), and diallyl sulfide
 (DAS)

 In-vivo, Adult Reducing lipid peroxidation and
 Reproductive Onion extract (0.5 mL/100 g
 Cadmium male albino increasing the antioxidant defense (19)
 toxicity BW/day, 7 days, p.o.)
 Wistar rats mechanism.
 In-vivo, male
 Cardiac Onion extract (1 mL, 30 Possibly through antioxidant and
 Cadmium Sprague-Dawley (18)
 toxicity days, p.o.). anti-apoptotic activity.
 rats

 6

Onion as an Antidote

Table 2. Continued.

 Study design and dose
 Type of
 Agent Type of study of garlic/garlic Effect demonstrated References
 toxicity
 component evaluated

 Onion extract (0.5 Reduced lipid peroxidation and
 In-vivo, Adult male
 Cadmium Hepatotoxicity mL/100 g BW/day, 7 enhanced antioxidant defense (55)
 albino Wistar rats
 days, p.o.) system.

 Onion extract (0.5
 Reproductive In-vivo, Adult male
 Cadmium mL/100 g BW/day, 7 Enhancement of antioxidant status. (56)
 toxicity albino Wistar rats
 days, p.o.)

 Onion extract (0.5 mL Protective effects via the reduction
 In-vivo, Adult male
 Cadmium Nephrotoxicity /100 g BW/day, 7 days, in LPO and enhanced antioxidant (8)
 albino Wistar rats
 p.o.) defense.

 Onion extract protected against
 Hepatotoxicity, Onion extract (1 Cd-induced atherosclerotic
 In-vivo, male Wistar
 Cadmium cardiovascular mL/100 g BW, 8 weeks, condition via a mechanism (57)
 rats
 toxicity p.o.) dependent on lipid peroxidation
 but not plasma testosterone level

 Onion extract attenuated the
 1 Onion extract
 Reproductive In-vivo, Adult male derangement of lipid peroxidation
 Cadmium (mL/100 g BW, 8 (54)
 toxicity Sprague-Dawley rats profile in testicular tissues caused
 weeks, p.o.)
 by CdSO4 exposure

 Onion skin extract protected yeast
 In-vitro, yeast strain cells from the occurrence of
 Cadmium Cell toxicity Onion skin extract (58)
 NCPF 3178 oxidative stress induced by
 cadmium

 Reduced lipid peroxidation in the
 Onion (600 and 300
 Cyanide Nephrotoxicity In-vivo, rats kidney and increased antioxidant (9)
 mg/kg BW/day)
 status

 Hydro-alcoholic extract
 Reduced lipid peroxidation in the
 of onion (5, 10, 20 and
 formaldehyde Nephrotoxicity In-vivo kidney and increased antioxidant (10)
 40 mg/kg/day14 days,
 status
 p.o.)
 Hypochlorous In-vivo, human Protective effects against oxidative
 Hemotoxicity Onion extract (59)
 acid erythrocytes damage.
 Heterocyclic
 In-vitro, immortal By the inhibition of activating
 aromatic Genotoxicity Onion juice (60)
 mammalian cells enzymes (CYP enzymes)
 amines
 Hydrogen In-vitro, WB-F344 rat
 Hepatotoxicity Onion flesh extract Antioxidant activities (61)
 peroxide liver epithelial cells

 In-vitro, Vero cells
 N-
 Nephrotoxicity (African green Onion Aqueous extracts Antioxidant activities (65)
 nitrosamines
 monkey kidney cells)

 Hepatotoxicity,
 Polar fraction of onion
 cardiotoxicity, In-vivo, Male Sprague-
 Lead oil (100 mg/kg/BW, 1 Antioxidant activities (63)
 and nephron Dawley albino rats
 month, p.o.)
 toxicity

 7

Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

Table 3. Protective effects of onion and its main constituents against drugs and health care products (consumer products) induced
toxicity.
 Table 3. Protective effects of onion and its main constituents against drugs and health care products (consumer products) induced toxicity.

 Study design and
 dose of garlic/
 Agent Type of toxicity Type of study Effect demonstrated References
 garlic component
 evaluated
 In-vivo, Male Onion juice (10.5
 Nephrotoxicity Antioxidative
 Potassium oxonate Sprague-Dawley g/kg/day, 14 (15)
 hepatotoxicity mechanisms
 rats days,p.o.)

 A. cepa (Onion)
 seeds (AC) extract
 Reproductive Adult male Wistar Antioxidative
 Streptozotocin (200 or 400 (12)
 toxicity rats, mechanisms.
 mg/kg/day, 28
 days, p.o.)
 In-vitro, human onion extract(10
 Bleomycin Cytotoxicity Antioxidant activities (20)
 lymphocytes, and 20 μl/ml)

 Increased cell
 In-vivo, male F344 Organosulfur proliferation with
 Diethylnitrosamine Hepatotoxicity (67)
 rats compounds increased poly‐amine
 biosynthesis

 Increased cell
 In-vivo, male F344 Organosulfur proliferation with
 Diethylnitrosamine Hepatotoxicity (66)
 rats compounds increased polyamine
 biosynthesis

 In-vivo, male Onion extract
 Enhancement of
 Doxorubicin Hepatotoxicity Sprague Dawley (1ml, 14 days, (68)
 antioxidant status
 rats p.o.)

 Ethanolic extract
 In-vivo, male of extract of onion Protecting the kidney
 Gentamicin Nephrotoxicity Sprague Dawley (200 and 400 from the oxidative (69)
 rats mg/kg, 14 days, stress
 p.o.).
 Reducing both
 intracellular ROS
 In-vitro, HT22
 Glutamate CNS toxicity Quercetin overproduction and (22)
 cells,
 glutamate-mediated
 Ca(2+) influx.

 inactivation of PKC- 
 induced by
 In-vitro, phosphorylating
 corticalneuronal ERK1/2 is responsible
 L-Buthionine sulfoximine Neurotoxicity Onion extract (2)
 cells derived from for the neuroprotective
 mouse embryos effect of Onion extract
 against BSO-induced
 oxidative stress

 Antioxidant property
 Cycloalliin )10, 20
 In-vivo, male reduced harmful
 Isoproterenol Cardiotoxicity and 30 mg/ kg, 30 (71)
 albino Wistar rats effects of ROS
 days, p.o.)
 generation

 8

Onion as an Antidote

 Experimental which differ in response to different preventive
 measures. Onion oil as a preventive measure
 In this review article, a comprehensive was efficient in the inhibition of C. botulinum
search was conducted for studies that have type A toxin production in meat, but it fails in
been published until March 27, 2019, in inhibition of type B and E toxin production
the following databases: PubMed, Web of (33).
Science, SciVerse Scopus, and Embase.
The following medical subject headings Clostridium difficile
and keywords, such as ‘Allium cepa’, Clostridium difficile (C. difficile) is a
onion, ‘protective effect’, antidote, venom, healthcare-associated infection that is usually
toxicity, cardiotoxin, cardiotoxic, neurotoxin, associated with antibiotic use. Two toxins are
hepatotoxic, hepatotoxin, nephrotoxin, the main factors responsible for symptom
nephrotoxic, mycotoxins, aflatoxin, genotoxic, contribution: toxin A and Toxin B. Aside from
lipopolysaccharide, and toxin were used. those two toxins, a third toxin is named binary
 toxin whose virulence is not fully known.
 Natural agents induced toxicity Reduced efficacy and recurrence have been
 Aflatoxin reported with the use of traditional treatment
 Aflatoxins are secondary metabolites (metronidazole and vancomycin) against C.
of certain strains of Aspergillus flavus and difficile. Fresh onion bulb extract has reduced
Aspergillus parasiticus (A. parasiticus) the production of all these three toxigenic
that have been associated with toxigenic, strains and inhibited toxin production by ≥
carcinogenic, mutagenic, and teratogenicity 40% in these strains (34).
to different species of animals (31, 32). In a Lipopolysaccharides (LPS)
study performed on sexually mature male LPS or endotoxins are one of the
Sprague-Dawley rats, the effect of aflatoxin components of Gram-negative bacteria’s
on these rats and possible antitoxic effects of outer membrane, consisting of lipid and
onion were examined. In this study, the rats polysaccharide. While in the body, it can affect
were fed contaminated aflatoxin food. The rise the immune system and cause septic shock
of ALT, AST, ALP, cholesterol, triglyceride, and inflammation. Also, it can modulate bone
total bilirubin, LDH, urea, creatinine, and remodeling by inducing bone resorption. This
creatinine kinase were considered. Albumin
 effect of LPS has been observed In-vivo and
and total protein also decreased in these rats.
 in-vitro. MC3T3-E1 (mouse preosteoblast cell
The co-treatment with oil-soluble extract
 line) cells were affected by LPS that showed
of onion in these rats ameliorated effects of
 promoted apoptosis. Quercetin is one of the
aflatoxin on serum biochemical biomarkers.
 main flavonoid components of A. cepa extract
Although aflatoxin almost did not affect
 (2). Pre-treatment and treatment of these
kidney and liver GSH content, it reduced SOD
 cells with quercetin decreased the number
activity and increased MDA levels. However,
 of apoptotic cells. With treatment, quercetin
onion extract ameliorated these effects (31).
 showed inhibitory effects on days 5 and 7,
 Clostridium botulinum but the effects of pre-treatment were present
 Clostridium botulinum (C. botulinum) is an after 24 h. Pre-treatment with quercetin also
anaerobic bacterium whose growth and toxin improved the number of calcified nodules
production in food causes hazardous syndrome compared to the non-treated group. The
in the human body and is responsible for several expression of osteoblast-specific genes (ALP,
emergency admissions. Several methods have Runx2, OSX, and OCN) also increased
been suggested as preventive measures of its in a dose-dependent manner with the pre-
growth in the food chain. Some ingredients application of quercetin. This pre-treatment
suggested for such use have been associated effect also extended to the caspase cascade.
with carcinogenesis. Contamination by C. Pre-treatment with quercetin increased the
botulinum might be caused by different depleted expression of B-cell lymphoma 2
subtypes of this bacteria, such as A, B, and E (Bcl-2) and B-cell lymphoma-extra large (Bcl-

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Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

XL) and decreased the enhanced expression dependent degenerative changes in the lung
of caspase-3, BCL2 Associated X (Bax), and and pulmonary tissues. Nicotine is the main
cytochrome c compared to the non-treated risk factor for many pulmonary diseases such
group. With or without the presence of LPS, as lung cancer and COPD. Administration of
quercetin enhanced the expression of these nicotine to Sprague-Dawley adult male albino
mitogen-activated protein kinase (MAPK) rats made their weight gain and lung protein
proteins: p-ERK1/2, Wnt3, and β-catenin depleted. It also increased the malondialdehyde
and done the opposite effect on p-p38 and (MDA) levels and decreased the activity of
GSK-3β protein levels. SP600125, PD98059, catalase (CAT), superoxide dismutase (SOD),
SB203580, XAV939, and the Wnt/β-catenin and the levels of glutathione (GSH) and
inhibitor attenuated all quercetin effects on epithelial lining fluid (ELF). Administration
MAPK proteins and also resulted in Bcl-2 and of onion extract following nicotine was
Bcl-XL enhancement as well as the opposite able to attenuate all the alterations made by
effects on caspase-3, Bax, and cytochrome c. nicotine. Though the alterations attenuated,
The quercetin effects on osteoblast-specific onion extract was unable to fully reverse
genes were also absent after such applications. these effects. In histopathological studies,
Dexamethasone application also resulted onion was unable to correct nicotine-induced
in attenuation of both LPS and quercetin changes including thickened interalveolar
effects on MAPKs and the protein expression septa, congested capillaries, and massive
of osteoblast-specific genes. From the data foamy macrophages. In semithin and ultrathin
mentioned here, it can be concluded that sections, foamy macrophages were the main
quercetin can protect the bone against LPS pathologic observation remained in onion
induced absorption and may even improve treated groups (14).
bone formation (21).
 In BV-2 microglial cells, LPS can decrease Naja naja karachiensis
cell viability and cause NO production. It also Pakistani cobra with the scientific name
increases COX-2 expression at the mRNA and of N. n. karachiensis is one of the poisonous
protein levels and proinflammatory cytokine snakes of southern Asia. This snake is one of the
(IL-6, TNF-α, and IL-1β) expressions. Pre- Elapidae family subgroups. N. n. karachiensis
treatment with methanolic extract of A. cepa envenomation can cause many complications
ameliorated all these effects and increased such as hypotension, edema, pain, paralysis,
BV-2 microglial cell viability. It also promoted necrosis, cardiac arrest, mucus discharge,
Bcl-2 expression which might be responsible bleeding gums, bleeding wounds, hematuria,
for its cell viability improvement effects. and coagulopathy. It also can induce acute
HO-1 and NQO1 mRNA expression also cardiac, hepatic, renal, and musculoskeletal
increased in the presence of A. cepa extract, toxicity. One of the many effects seen after
which has the potent capability to detoxify this snake envenomation is hemolysis. This
harmful compounds, combat reactive oxygen snake’s venom seems to destabilize the human
species, and directly or indirectly modulate the red blood cell (HRBC) membrane. This effect
BBB permeability, immune system, as well as may be caused by phospholipase A2 (PLA2),
inflammatory response. A. cepa extract also protease enzymes, and partly 5’-nucleotidases.
increased catalase mRNA expression. The The bulbs of A. cepa were found helpful to
methanolic extract of A. cepa also improved neutralize snake venom hemolysis. A. cepa
cell viability in the presence of 1-methyl-4- was able to inhibit PLA enzyme 76% and
phenylpyridinium (another toxic compound neutralize PLA2 hydrolytic activity at a rate of
for BV-2 microglial cells) (34). 50% at all concentrations, but it failed to inhibit
 5’-nucleotidases activity (35-37). Onion was
 Nicotine able to normalize CK-MB enhanced levels
 Nicotine is a natural alkaloid with potent after N. n. karachiensis envenomation (38).
parasympathomimetic effects. Its main route These effects of onion may be due to HRBC
of exposure for humans is through tobacco membrane stabilization (39).
smoking. Nicotine was shown to exert dose- The onion was also effective against bee

 10

Onion as an Antidote

sting symptoms. In a study in Turkey, Halil brain tissue. Aluminum chloride chronic
et al. mentioned that one of the preferred exposure increases AChE activity, vacuolation
alternative treatment methods against life- in the hippocampal region (and deterioration of
threatening events resulting from bee stings hippocampus), and decreases pyramidal cells,
by beekeepers is applying onion on the sites GSH, and catalase activity. Administration
of the sting (40). of A. cepa along with aluminum chloride,
 chronically, ameliorate all behavioral,
 Chemical induced toxicity histological, and biochemical changes. It also
 Industrial chemicals reduces abnormal aluminum deposition in
 Acrylamide (ACR) brain tissue (45). Aluminum also increases
 ACR is a carcinogenic compound and is SOD activity and MDA level and decrease
widely found in cigarette smoke, fried and CAT, GR, and GPx activity and levels of GSH
baked foods, carbohydrate foods, and also in brain tissues. These differences are also
cosmetics. ACR is used in various industries, present in gene expressions. Quercetin, an
such as soil coagulation, wastewater onion component, ameliorated such effects.
management, dye synthesis, and laboratories This may indicate that these constituents
for gel electrophoresis (43, 44). possess the neuroprotective ability and can pass
 The routes from which ACR causes its the blood-brain barrier and exert direct effects
carcinogenic effects are not fully known. It on brain tissue (46). Quercetin metabolites
can reduce cellular antioxidant capacity and have been found to inhibit the transcription
also interfere with DNA transcription and of genes such as S14, FAS, apolipoprotein
repair. Isolated Botli fish liver cells decreased CIII, and transferrin (45, 47). This inhibition
the absorbance of NR (neutral red), MTT might be responsible for decreased aluminum
(mitochondrial dysfunction), CV (cell wall deposition in the brain, as its transfer to the
membrane integrity), and PA (immunotoxicity) brain is primarily transferrin mediated (45).
assays. Treating with onion peel extract (OPE) Arsenic
was able to attenuate the ACR toxic effects. Arsenic is a heavy metal and able to form
This attenuating function of OPE was recorded toxic compounds. It usually contaminates
to be a dose-dependent effect and at a dosage groundwater and its toxicity is manifested
of 20 mg/L, it was able to wipe out these by nephrotoxicity and renal tissue changes.
effects completely. Treatment with PEG-SOD Its exposure also causes Bowen’s disease,
(a superoxide scavenger) and PEG-catalase (a squamous cell carcinomas, melanosis, and
hydrogen peroxide scavenger) showed similar hyperkeratosis. Arsenic exposure might
effects as OPE in acrylamide exposed liver increase conjugated diene effects in brain
cells which indicate hydrogen peroxide and and liver tissues and decrease SOD and CAT
ROS roles in acrylamide induced cell toxicity. activity as well as glutathione levels. It also
These findings also indicate that OPE may results in cytochrome c protein release in the
also implicate its protective effects in liver brain and liver and deposits in these tissues.
cells by promoting antioxidant capacity or While subcutaneous treatment with quercetin
either preventing formation of ROS (16). seems ineffective, the administration of
 liposomal quercetin ameliorates arsenic toxic
 Aluminum (Al)
 effects and reverses histological changes via
 Al is a metal element that can cause
 antioxidant effects. Such effects might also be
toxic effects in different organs, mostly
 due to quercetin’s ability to restrict molecular
in the nervous system. Al can be found in
 transfer in the blood-brain barrier and its
manufactured foods, medicines, cheese, tea,
 chelating abilities. With such mechanisms,
cosmetics, and is also added to drinking water quercetin can decrease arsenic presence in the
for purification purposes (45, 46). cellular environment (48).
 Aluminum with chronic uses can cause
changes in behavior, motor coordination, Carbon tetrachloride (CCl4)
and memory performance. Biochemical and In one study carried out on male adult
histological changes were also observed in Wistar albino rats, the protective effects of

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Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

a phenolic-rich extract of red onion peels alcohol toxic effects in the liver, it could be
on CCl4 toxicity were examined. Carbon suggested that onion might be able to protect
tetrachloride was able to increase hepatic against alcoholic fatty liver. Although onion
enzymes: AST, ALT, ALP, and GGT. It also extract was able to reduce these amounts,
reduced albumin levels and changed lipid it was not able to return them to the control
profiles. The TG, total cholesterol, LDL-C, levels (11).
and VLDL-C levels raised and HDL-c levels One of the components that might be
decreased in rats. Creatinine, uric acid, urea, involved in onion protective effects is fisetin (3,
and calcium levels also increased following 3′, 4′, 7-tetrahydroxyflavone) at concentrations
CCl4 treatment liver and kidney MDA level of 2–160 µg/g. Fisetin is a bioflavonoid with
increased and tissue non-protein sulfhydryl antioxidant, anti-inflammatory, anticancer,
(NP-SH) and total protein synthesis capacity antihyperlipidaemic, and neuroprotective
decreased. Pre-administration of the phenolic- properties. Feeding male C57BL/6 mice with
rich extract of red onion peels was able to 5 doses of 50% ethanol orally was able to
ameliorate all these effects while failed to increase serum AST and ALT levels and also
restore pretreatment status. Its effects on all liver weight. Unlike liver weight, body weight
parameters were almost dose-dependent but decreased following ethanol use. Catalase,
on albumin, a dose-dependent effect was not SOD, GSH, glutathione-S-transferase (GST),
seen (49). glutathione reductase (GR), vitamin C, and
 NQO1levels were also reduced in alcohol-
 Ethanol affected mice. The hepatic thiobarbituric acid
 Ethanol is obtained from the fermentation reactive substances (TBARS), nitrite, carbonyl
of sugars in vegetables, fruits, and cereals content, and OH-1 expression increased.
which has played a key role in medical and Also, the amount of MMP-9, pro-MMP-2,
industrial practices, and alcoholic beverages and active MMP-2 increased both in serum
include beer spirits and, wines. Ethanol could and tissue following alcohol consumption
affect various parts of the body including the along with collagen deposition. Mitochondrial
liver, heart, brain, kidney, skeletal muscle, and indicators such as NDH, SDH, COX, GSH,
pancreas (50-52). and MTT reduction assay showed a reduction
 Fatty liver is the most common liver disease in alcohol-affected mice too. Surprisingly,
in western countries and probably the whole pretreatment with fisetin was able to attenuate
world. Almost 45% of individuals are affected all the toxic effects of ethanol-fed mice.
by some degree of fatty liver, 20% of which It also was able to decrease the increased
are due to alcoholic fatty liver. Alcoholic nuclear factor κB (NF-κB) levels in these
fatty liver, in turn, can cause hepatic steatosis, mice. Fisetin also protected the liver tissue
fibrosis, and cirrhosis. Studies showed that against histopathological changes seen in
alcoholic fatty liver cannot be prevented by alcohol-treated mice (hepatocyte degeneration
the use of different dietary supplements except with vacuolization and hemorrhagic lesions,
for onion and garlic oil. Feeding albino rats inflammatory cell infiltration, mild necrosis,
with 3 mL of 25% ethanol per 100 g body and fibrosis). These findings may suggest
weight intragastrically were able to raise fisetin as the onion’s responsible component
triacylglycerol and total cholesterol levels in reducing the effects of alcohol on fatty liver
in serum and liver. Also, liver MDA levels and protecting against it (1).
reduced the following alcohol consumption.
But there was no change in Liver aspartate Benzopyrene (BaP)
aminotransferase (AST), alanine transaminase BaP is an aromatic hydrocarbon with potent
(ALT), and alkaline phosphatase (AlkP). Using mutagen and carcinogen activity. It is mainly a
aqueous extracts from 300 mg onions per 100 product of organic compound combustion. Its
g body weight along with the named alcohol main routes of exposure are cigarette smoke,
regiment decreased the rise of triacylglycerol an air pollutant, and fuel combustion (53).
and total cholesterol levels in serum and liver BaP is known for its involvement in lung
compared to alcohol-fed rats. By attenuating and forestomach neoplasia. BaP administration

 12

Onion as an Antidote

can increase MNPCEs (micronucleated SOD activity, CAT activity, and ALP activity
polychromatic erythrocytes) in mice bone depleted. Administering onion extract to these
marrow. Diallyl trisulfide (DAT), diallyl rats was able to attenuate sperm characteristic
sulfide (DAS), allyl methyl trisulfide (AMT), parameters and also improve MDA, GSH,
and allyl methyl disulfide (AMD) all are SOD, and CAT alterations. The effects exerted
unsaturated organosulfur compounds found on enzyme and oxidant parameters by onion
in onion and garlic. These compounds contain extract in Cd-exposed rats showed a dose-
allyl groups in their structure. DAT and AMT dependent pattern. Also, GST activity changed
could prevent the formation of the forestomach following Cd administration. GST activity
adenoma in A/J mice with no effect on increased by both Cd and onion extract. Onion
pulmonary adenomas. DAS showed exactly effects on the testis weight weren’t significant
the opposite effect, with effectiveness against and it failed to reverse the cadmium effect.
pulmonary adenomas, while AMD effectively Onion in the absence of Cd was also able
inhibited tumor formation in the forestomach to reduce the number of abnormal sperms
and lung. Interestingly, all of the compounds significantly. Such observations show
effective in inhibition of forestomach tumor that onion can protect male albino rat’s
formation were able to increase GST content. reproductive system against Cd toxicity (19).
In the liver and small intestine, AMT, AMD, In another research performed on Sprague-
DAT, and DAS increased GST content Dawley rats, fresh onion extract pretreatment
too. None of these effects were observed proved efficient in protecting against testicular
in saturated analogs which contain propyl weight loss. It also reversed cadmium toxic
instead of the allyl group. DAS and AMD, effects on sperm count, motility, morphology,
both compounds with three sulfur groups, testicular SOD, and CAT activity. Protection
showed effectiveness against pulmonary against the rise of MDA levels in the testis was
adenoma, while disulfide compounds, DAT also reported in these rats (54).
and AMT, have not shown such effects. This Onion sulphur compounds also may have
may indicate that the number of sulfur atoms the potential in reducing Cd-induced hepatic
may be of importance in the site they are damage. It has been observed that they can
present or effective. These findings suggest attenuate histopathological changes (focal
that allylic compounds present in onion and necrosis, inflammatory cell infiltrations,
garlic may have protective effects against BaP and giant cell formation), serum and tissue
carcinogenesis (17). biochemical alterations, enzymatic antioxidant
 capacity deterioration, lipid and protein
 Cadmium (Cd) peroxidation, and also Cd concentration. In the
 Cd is a heavy metal that is known as an kidney, DTS (diallyl trisulfide) showed similar
environmental contaminant usually present effects and exhibited cytoprotective functions.
in low concentrations. Cd exposure has been The same effects have been observed by DTS
boosted by its use in industrial sectors and in brain tissue. DTS was also able to restore
also tobacco use. Cd can cause liver and AChE and membrane-bound enzymes. Onion
kidney injury, disruption of the endocrine also was able to restore albumin and lipid
system, anemia, diabetes, respiratory diseases, profile. These effects of onion seem to be
neurological disorders, skeletal system related to its effects on antioxidant capacity
damage, gonadotoxic and spermatotoxic and lipid peroxidation (13). In the heart tissue,
effects. These toxic effects are mostly Cd can also cause lipid peroxidation, resulting
attributed to ROS formation by Cd (19, 26). in elevated MDA levels, which in turn could
 In male albino rats, Cd exposure tends be attenuated by A. cepa administration.
to reduce testis weight. The concentration SOD, CAT, and glutathione peroxidase
of sperms in the epididymis, sperm motility, (GSH-Px) activities were also reduced by
abnormal sperm count, and proportion of Cd exposure. The prevalence of apoptotic
live sperm to dead sperm also reduced in cardiomyocytes elevated too. These changes
the rats treated with Cd. Testis MDA level induced histopathological alterations, such as
increased in Cd -exposed rats, and GSH level, myofibrillar loss, vacuolization of cytoplasm,

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Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

and irregularity of myofibrils. A. cepa was coadministration of these two compounds
also able to attenuate enzymatic antioxidant shows that onion extract can attenuate Cd
alterations in the heart and reduce apoptosis. It effects on ACPtotal and ACPprostatic both
also reduced histopathological changes caused in plasma and prostate gland. From these
by Cd. These changes could be due to ROS observations, it can be concluded that onion
formation and lipid peroxidation which can can protect the prostate gland against Cd
be reversed by A. cepa exposure. Although toxic effects (56). In another study, adult
A. cepa almost attenuated all the observed Wistar rats treated with Cd, showed lesser
altered parameters, it seems it couldn’t weight gain compared to control. Kidney
prevent Cd-induced cardiac impairment (18). weight also decreased in rats exposed to Cd,
Following Cd administration to the rats, which tend to reverse while Cd administration
MDA levels increase and GSH, SOD, CAT, concurred with onion extract administration.
and GST activities deplete. These alterations The kidney MDA level tends to increase by
compensated dose-dependently by onion Cd administration, while onion administration
extract administration. Also, onion alone alone decreased these levels. Also, Cd and
tends to increase SOD, CAT, GSH, and GST onion extract co-administration showed lesser
levels while administered alone. This effect MDA levels in comparison to the Cd group
was present only in high doses for SOD and alone. GSH level along with SOD and CAT
CAT and such effects have not been observed activity showed a similar pattern of alteration.
in accordance with AST and ALT. But the GSH, SOD, and CAT levels were enhanced
onion was able to reduce plasma AST and with onion extract exposure alone in a dose-
ALT increased levels caused by Cd. It also dependently pattern and were depleted after
increased the AST and ALT activity levels Cd administration. Also, co-treatment with
in the liver tissue which again decreased by both compounds showed the attenuation of
cadmium exposure. Although onion has mild Cd effects. GST levels increased after both
but not significant effects on hepatic ALP Cd and onion administration, but the changes
activity, it has a significant effect on alkaline following onion exposure were not significant.
phosphatase (ALP) in the Cd -exposed rats. Coadministration of both compounds again
From what is mentioned above it can be tends to show amounts similar to the control
concluded that Cd toxic effect can be almost group, which itself shows the reversal of
compensated by onion extract administration Cd effects. In accordance with renal Na+/
(55). Cd is also a potential risk factor for K+-ATPase activity again onion extract
prostate malignancy. It has been shown that and Cd showed the opposite effect. Onion
Cd administration can decrease the weight enhanced renal Na+/K+-ATPase activity and
of the prostate gland while increasing MDA Cd decreased activity. In this case, also pre-
levels and depleting GSH levels, SOD, and administration of onion extract in the Cd
CAD activities. Although treatment with onion challenged group showed a tendency to the
extract fails to retrieve prostate weight, it was enhancement of renal Na+/K+-ATPase activity.
successful in attenuating MDA levels and also It seems that onion extract pretreatment tends
increasing the activity of SOD and CAT along to partially compensate for lipid peroxidation
with GSH levels, dose-dependently. Onion and antioxidant activity depletion caused by
alone also can exert the same effects on GSH Cd and therefore shows protective effects
levels, SOD, and CAT activity. Interestingly, against Cd toxicity (8). Cadmium in male
both Cd and onion alone, increased activity of Wistar rats can cause hepatic and renal
GST but in the presence of cadmium, onion damage. Research on the effect of onion
tends to decrease GST activity and attenuate extract on cadmium toxic effects showed
Cd effects. Cd tends to decrease total and that A. cepa extract ameliorated cadmium
prostatic acid phosphatase activities (ACPtotal effects on body, liver, and renal weight and
and ACPprostatic) in the prostate and increase also abrogate its effect on serum lipid profile
these amounts in plasma. Onion alone does not (cholesterol, TG, HDL, and LDL). Although
affect plasma ACPtotal and ACPprostatic, but A. cepa was able to reduce many toxic effects
it exerts Cd opposite effects in plasma. Also, of cadmium in male Wistar rats, it could not

 14

Onion as an Antidote

reduce the Cd’s effects on plasma testosterone particles exert many toxic effects on the
(57). Also, a study concerning onion skin human body. They are responsible for many
extract (contain phenolic compounds such respiratory problems. They also might exert
as quercetin) effect on cadmium toxicity in a toxic effect on other organ systems. There
Saccharomyces cerevisiae has shown similar is data indicating diesel exhaust particles
protective effects. In this study, onion skin might also exert toxic effects on the male
extract has been able to reduce ROS, OH- and reproductive system. Onion powder and also
O2- levels dose-dependently. It also increased its quercetin content might be of protective
GSH levels and reduced MDA levels dose- value alleviating such toxic effects. It has
dependently. Although its effects on SOD, been observed that administration of onion
CAT, and GPx were dose-dependent, it was powder or quercetin might protect daily sperm
almost restricted to basal activity levels in the production, sperm morphological changes,
control group (58). and also the number of Sertoli cells (4).
 Cyanide (CN) Hypochlorous acid (HCLO)
 CN is a fatal poison found in several forms HCLO physiologically is produced in
in the environment. It could be also found the body via neutrophil and monocytes after
in several plants. When entering the body it inflammatory tissue injury. Upon exposure,
can inhibit cellular oxygen utilization, induce HCLO can cause osmotic fragility and produce
reactive oxygen species (ROS) formation, and transient membrane pores in RBCs. This
cause death (9). HCLO exposure may result in erythrocyte
 Several organs can be affected by CN, hemolysis (59).
such as the brain, blood, liver, and kidney. A Onion extract application 45 min
group of researchers administered CN to male before the HCLO exposure in the in-vitro
albino rats to investigate the onion’s capability condition could be able to reduce hemolysis.
in protecting against sub-acute CN toxicity While the effect for coppery onion (COM:
in the kidney. After CN exposure, relative Coppery Onion from Montoro) was lower
kidney weight increased in rats. Also, it raised than red onion (RTO: Red Tropea onion)
serum urea and creatinine level while reducing the difference wasn’t significant. Also, the
these amounts in urine. Kidney MDA levels HCLO administration reduced GSH content
increased while SOD, CAT, GST, and GSH and increased CAT activity. The application
activities depleted. Co-administration of onion of both onion extracts was able to attenuate
extract with CN attenuated all these effects. the HCLO effect on both parameters. Also,
In the presence of onion extract along with Onion extract was able to reduce low-density
cyanide SOD, CAT, GST, and GSH activities lipoprotein (LDL) oxidized levels. It seems
improved as well as MDA levels depleted. that onion antioxidant activity has a relation
Also, creatinine and urea levels both in blood with its polyphenolic content. Although ROT
and urine showed amounts closer to normal. has greater amounts of polyphenols, it seems
CN administration also made histopathological that in equal concentrations of polyphenols,
changes, such as acute tubular necrosis. These COM polyphenols have greater antioxidant
changes were absent in high doses of onion effects (59).
extract (600 mg/kg) and only mild focal
tubular necrosis was present in low doses (300 Heterocyclic aromatic amine (HAA)
mg/kg) used in the experiment. From what has HAA, potential human carcinogens, is
been observed in this study it can be suggested found in cooked meat and fish (60). High
that onion extract as an antioxidant capacity heat exposure seems to be the reason for the
improving agent can reduce many CN toxic formation of such compounds. 2-amino-
effects and therefore, offer some protection 3-methylimidazo[4,5-f]quinoline (IQ) and
against CN toxicity (9). 2-amino-1-methyl-6- phenylimidazo[4,5-b]
 pyridine (PhIP) are two of these HAAs,
 Diesel exhaust particles found in a human dietary regiment. To apply
 It is no question today that diesel exhaust their genotoxic effects, HAAs need to be

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Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

activated by CYP enzymes. Phase II enzymes and the mixture of these polyphenols showed
can also reduce the genotoxic activity of successful results in the DPPH test. Also,
their metabolites. Both these compounds can quercetin effect was higher compared to rutin,
be activated by V79 Chinese hamster lung and isorhamnetin, and even OPE in equal
fibroblasts. In in-vitro exposure of these cells doses, which highlights the importance of
to HAAs, onion extract showed high inhibitory quercetin as the main polyphenol that exists in
effects on IQ genotoxic effects, while it onion peel. H2O2 exposure also increases the
was only weakly active against genotoxic density of P3 band of Cx43, which suggests
effects of BaP-7,8-diol. Surprisingly, onion the enhancement of Cx43 phosphorylation
extract could only weakly inhibit N-OH-IQ by H2O2. While OFE does not affect P3 band
genotoxicity (60). density, OPE dose-dependently reduced the
 P3 amounts, which indicating the suppression
 Hydrogen peroxide (H2O2) of Cx43 and ERK1/2 phosphorylation (61). In
 H2O2 is a colorless liquid with slight acidic another study, the genotoxicity and lifespan
properties. It is a chemically unstable molecule, effects of onion were checked in Drosophila
naturally produced in the body with powerful melanogaster, and its DNA-clastogenic,
oxidizing quality. Using SOD H2O2 forms and pro-apoptotic, and cytotoxic activities were
by the use of catalase, it turns to water and analyzed using HL60 tumoral cells. The
oxygen. While H2O2 is used by the cells in the lyophilized onion was non-genotoxic and
catabolism of different molecules, its presence antigenotoxic against H2O2-induced DNA
in other cellular spaces might be hazardous. For damage with a positive clear dose-response
example, in intracellular space, it can inhibit effect and showed no positive effects on flies’
gap-junctional intercellular communication lifespan and healthspan (62).
(GJIC). Onion and especially its peel is rich
in antioxidants and hypothetically can protect Lead (Pb)
the body against excessive amounts of H2O2. Pb is a hazardous metal element with toxic
Applying onion peel extract on WB-F344 neurological, behavioral, immunological,
RLE (rat liver epithelial cell line) culture in renal, ‎hepatic, gastrointestinal, reproductive,
the presence of H2O2, Kim et al. investigated circulatory, and especially hematological
the protective effects of onion peel extract effects. Pb ‎exposure during the pregnancy
(OPE) on H2O2 inhibition of GJIC and period is very harmful and causes a broad
compared it with onion flesh extract (OFE). range of biochemical, ‎physiological, and
H2O2 at a concentration of 100 μM was able behavioral dysfunctions in the offspring. This
to suppress GJIC by 50%. Pretreatment with heavy metal is considered as one of the most
OPE was able to restore GJIC at 500 and common ubiquitous and industrial pollutants
1000 μg/mL, with almost complete restoration that are toxic even at low concentrations
with 1000 μg/mL; however, the same doses and exert extensive damages to the tissues.
of OFE were unable to restore GJIC. It is There is data suggesting that Pb ‎might exert
also consistent with the polyphenol and some of its effects by causing oxidant stress
flavonoid amounts present in these extracts. indirectly. Through oxidative stress lead might
OPE contains 44 times polyphenol and 183 decrease blood Hb, RBC, and WBC counts
times flavonoid compared to OFE. In the and ʠ-ALAD in rats.
1,1-Diphenyl-2-picrylhydrazyl (DPPH) assay, There are observations suggesting onion
OPE’s half-maximal inhibitory concentration oil may alleviate such effects, even in
(IC50) was 148 μg/mL and showed lesser comparison to antioxidants such as vitamin E.
antioxidant activity compared to vitamin C. These superior effects extend to the protection
in the same test OFE showed no significant of blood and tissue GSH level along with
antioxidant activity, which may be indicative antioxidant enzymes, such as CAT, SOD, GR,
of the absent extracellular antioxidant activity and glutathione peroxidase against harmful
in OFE. Kim et al. also repeated DPPH assay lead effects. Lead is also able to increase lipid
for the major polyphenols of OPE quercetin, parameters, such as serum total cholesterol,
rutin, and isorhamnetin. Both quercetin alone LDL, cholesterol, and TAG as well as tissues.

 16

Onion as an Antidote

It also increases TBARS levels in tissues. In these parameters. But the effects of onion
this regard, onion is as effective as vitamin E. extract did not show a specific dose-dependent
It also might help tissues, such as the liver and pattern or even a maximum efficient dose. The
kidney to regenerate (63). onion extract in all doses also decreased blood
 urea levels with the most reduction at a dose
 N-nitrosamines of 5 mg/kg. But in the case of creatinine, onion
 N-nitrosamines are an important class of could only inhibit the increased parameter in
chemical carcinogens that occur in human 10 mg/kg dosage, and all other administered
nutrition and other surroundings media and dosages (5 mg/kg, 20 mg/kg, and 40 mg/
can be synthesized endogenously in the body kg) it increased blood creatinine even more.
(64). Pathologically, CH2O caused the glomerular
 Administration of four N-nitrosamines, collapse and sclerosis via tubular necrosis
N-nitrosodimethylamine (NDMA), and vacuolization with no interstitial tissue
N-Nitrosopyrrolidine (NPYR), changes. Adding onion extract to the treatment
N-nitrosodibuthylamine (NDBA), and caused the tubular and glomerular changes
N-nitrosopiperidine (NPIP) to Vero cells to fade in a dose-dependent manner but
along with onion aqueous and ethanolic vascular changes were present in low doses,
extracts, showed that both onion extracts which also fade via an increase of the dose.
were able to reduce the cytotoxic effects of Concerning these findings, we cannot claim a
the N-nitrosamines. The aqueous extract definitive protective or synergistic effect for
showed only effects on NDMA and NPYR onion alcoholic extract regarding the kidney
in the aqueous extract. At doses of 0.6-3 mg/ protection against CH2O. Also, the effect of
mL, there was an increase in cytotoxicity onion extract on the antioxidant activity of
but at doses of >3 mg/mL, anti-cytotoxic renal cells and the effect of pretreatment with
effects were observed. At 4-6 mg/mL, it also onion extract remain unknown and require
stimulated cell proliferation. The ethanolic a broader investigation to show the effect of
extract showed effects on all four nitrosamines onion in CH2O toxicity (10).
with dose differences as follows: >2.5 mg/mL
for NPIP and >4 mg/mL for NPYR. At doses of Drugs and health care products
30-40 mg/mL, it stimulated cell proliferation. (consumer products)
It seems that onion extracts in both forms are
protective against N-nitrosamines toxicity and Diethylnitrosamine (DEN)
carcinogenicity (65). DEN is a carcinogenic and mutagenic
 chemical compound soluble in water, lipids,
 Formaldehyde (CH2O) and other organic compounds. It is used as a
 CH2O is a highly reactive natural gas gasoline and lubricant additive, antioxidant,
compound that is flammable and soluble in and stabilizer for industry materials. When
water. It is the simplest form of aldehydes heated it can release nitrogen oxides and also,
and is used as a disinfectant, also as an it may damage DNA integrity by alkylation.
additive in cosmetic products and some other Also, DEN is a known liver carcinogen. To
industrial purposes. CH2O can adversely affect investigate onion organosulfur compounds’
cardiovascular, neurological, gastrointestinal, potency in protecting the liver against DEN
respiratory, and renal systems. There is a group of researchers designed a study.
evidence supporting the CH2O role in renal Bodyweight in DEN-treated rats decreased;
carcinogenesis. When administered to however, dihydropyrimidine dehydrogenase
laboratory rat models, CH2O caused kidney (DPD), diallyl trisulfide (DAT), and PS
volume, glomerular volume, the number of prevented this effect. But relative liver
glomeruli to reduce, and blood creatinine weights depletion increased with diallyl
and urea to increase. According to kidney disulfide (DDS), dipropyl sulfide (DPS),
and glomerular volume and the number of diallyl trisulfide (DAT), allyl methyl trisulfide
glomeruli, an alcoholic onion extract showed a (AMT), methyl propyl disulfide (MPD),
reduction in CH2O adverse effects by increasing propylene sulfide (PS), and diethyl disulfide

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Dorrigiv M et al. / IJPR (2021), 20 (1): 3-26

(DMD) and decreased with DPD. Glutathione DOX hazardous effects, it can attenuate these
S-transferase placental form (GST-P)- positive effects and offers some amounts of protection
areas increased with DAS, AMS, and DPS against DOX hepatotoxicity (68).
treatment with the most efficacy seen in DPS
treatment (66). The same group investigated Gentamicin
different organosulfur (DPT, DMT, AM, and Gentamicin is a famous aminoglycoside
IAIE). Bodyweight was not significantly antibacterial agent with potent and widespread
decreased in the DEN-treated rats, exposed uses. The most restricting side effect of this
to DPT and DMT, and also liver weight drug is nephrotoxicity. The nephrotoxicity
increased with all organosulfur but the change caused by gentamicin was manifested by
with DMT, AM, and IAIE was only significant tubulopathy. In a study, the protective effects of
compared to DEN control group. Numbers A. cepa on gentamicin-induced nephrotoxicity
and areas of GST-P-positive foci per unit area in Sprague Dawley rats were investigated.
of liver sections after DEN initiation, GST-P Gentamicin administration caused the
positive areas and numbers for IAIE increased bodyweight to deplete and kidney weight
significantly. In the case of DPT and AM only to increase. The administration of ethanolic
numbers of GST-P-positive foci improvement extract of A. cepa (EEAC) dose-dependently
were significant, which suggest that these attenuated these effects of gentamicin. Also,
compounds may increase the probability of EEAC reduced serum creatinine which
liver tumor formation (67). increased by gentamicin dose-dependently.
 The serum total protein levels increased
 Doxorubicin (DOX) with gentamicin exposure. EEAC once again
 DOX is an antibiotic agent widely used in attenuate this effect. Histopathologically,
oncologic treatments. It is of use against blood the group affected by gentamicin showed
neoplasms, such as leukemia, lymphoma, and epithelial lining degeneration, faded by EEAC
some solid tumors. DOX exerts its effects via administration. From these results, it can be
blocking the cell cycle and inducing apoptosis. concluded that onion ethanolic extract can
DOX also has some adverse effects such as prevent gentamicin-induced nephrotoxicity
cardiotoxicity and hepatotoxicity. These (69).
adverse effects seem to be the result of ROS
formation and imbalance in cellular antioxidant Glutamate (Glu)
activity due to DOX exposure. Using Sprague– Glu is a neurotransmitter by which
Dawley rats as animal models, a group of nerve cells send their signals to other cells.
researchers studied DOX hepatotoxicity and Studies suggest that glutamate can induce
A. cepa protective effects against it. Following oxidative stress that can activate mitogen-
DOX administration, ALT and AST levels rose activated protein kinase (MAPK) pathways.
but with A. cepa pretreatment, ALT and AST These pathways interact with many cellular
levels declined even below the control group processes, such as cell growth, differentiation,
stats. Hepatic tissue MDA levels also rose inflammation, and cell death. Glu at a
and the levels of GSH and activities of SOD concentration of 5 mM can decrease cell
and GSH-Px reduced. In all these parameters, viability significantly. Also, cell apoptosis
although A. cepa extract was unable to and ROS formation in rat hippocampal cell
reverse the changes, it successfully attenuated cultures increased significantly after exposure
the alteration. It also protected against the to 10 mM of Glu. As it has been confirmed Glu
histopathological changes seen with DOX could induce a rapid Ca2+ influx. As a result,
administration: congestion and thrombosis of Glu increased the levels of calpain expression
central vein, degeneration and pleomorphism and reduced spectrin. As decreased JC-1 was
in hepatocytes, cytoplasmic eosinophilia, observed in the cell cultures it can be concluded
parenchymal necrosis, the proliferation of that Glu also disrupts mitochondrial membrane
biliary duct, focal necrosis, and inflammation integrity. Also, the Bcl-2 and Bid levels
in portal space. Finally, it could be said that decreased in the studied HT22 cells and Bax
even though A. cepa can’t make a setback for levels showed a slight increase. Pretreatment

 18