A Systematic Review on Oxidant/Antioxidant Imbalance in Aluminium Toxicity
The purpose of this study was to provide a systematic review on the animal or human evidences linking aluminium (Al) toxicity to oxidant/antioxidant imbalance. Embase, Scopus, Pubmed, Web of Science, Google Scholar and SID databases were searched up to 1st October 2010. Over 50 studies including animal and human linking oxidative stress to Al were reviewed. Most of animal and human studies show a significant increase in lipid peroxidation (LPO) by Al. The maximum LPO was reported in the brain. Data about changes of enzymatic antioxidants such as Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx) post exposure to Al are controversial. Animal studies showed that vitamin E, C, melatonin and pinoline reduce LPO in Al-exposed subjects. Al can affect body oxidant/antioxidant balance in favor of oxidative toxic stress. Among parameters tested in various studies, LPO seems the best indicator of Al toxicity. The role of iron homeostasis in mediation of cytotoxic effects of Al seems important. Since, oxidant/antioxidant imbalance is involved in the pathogenesis of many diseases including inflammatory bowel diseases, diabetes, osteoporosis, it would not be surprising to track roles of Al in many deliberating diseases in future.
Received: July 02, 2010;
Accepted: August 04, 2010;
Published: November 16, 2010
Oxidative Stress (OS) can be defined most simply as the imbalance between the
production of Reactive Oxygen Species (ROS) capable of causing peroxidation
of lipid layer of cells and the bodys antioxidant defense (Halliwell
and Gutteridge, 1997). Excessive generation of ROS leads to damage of cellular
lipid membrane, proteins and DNA. Several mechanisms exist in the body to cope
overproduction of free radicals. The basic and the most prominent defense mechanism
of the human body is antioxidants that are involved in prevention, repairing
and physical defense against oxidants. Antioxidants are generally categorized
to non-enzymatic and enzymatic. Non-enzymatic antioxidants include dietary compounds
(vitamins C and E), minerals (selenium and zinc), glutathione, uric acid and
ubiquinol. Superoxide Dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase
(GPx) are the main enzymatic antioxidants (Abdollahi et
al., 2004; Rezaie et al., 2007).
Metals as a part of the earth crust are redistributed naturally in the environment
by both geologic and biologic cycles. Although, elements can be toxic at high
doses but some of them are essential components of biological structures. Recent
studies have shown that metals can produce ROS resulting in Lipid Peroxidation
(LPO), DNA damage, depletion of sulfhydryls and altered calcium homeostasis.
Generally toxicity of metals specially the transition metals is mediated through
generation of ROS, LPO, DNA cleavage and decrease in antioxidant potential (Malekirad
et al., 2010).
Aluminium (Al) is the most abundant metal and the third most common element
in the earth crust. Although, Al is a common constituent of the environment,
it has no recognized biological function in the body. Unfortunately, the sources
of Al are largely unknown to the public. In addition to occurring naturally
in food and water, Al is added to drinking water, many processed foods, cosmetics,
toothpaste, antiperspirants and adjuvants in various parenteral preparations
and pharmaceutical agents (Becaria et al., 2002;
Pournourmohammadi et al., 2008).
Al is considered a pro-oxidant and in exposure results in the production of
free radicals (Halliwell and Gutteridge, 1990; Ranjbar
et al., 2008), being responsible for neurotoxicity. Al induces OS
by changes in the levels of SOD, CAT and biomarkers of cellular peroxidation
(Yousef, 2004). There has been considerable debate in
role of chronic exposure to Al in neurodegenerative disorders such as Alzheimer
(Zatta, 2006; Gupta et al.,
2005), Parkinson disease and dementia (Erasmus et
al., 1995) and hepatotoxicity (Chinoy and Parker,
1999). The toxic effects of Al appear to be mediated, at least in part,
by free-radical generation (Moumen et al., 2001;
Anane and Creppy, 2001).
In this systematic review, all evidences from animal and human studies relating toxicity of Al and OS were evaluated.
MATERIALS AND METHODS
Data sources: Embase, Scopus, Pubmed, Web of Sciences, Google Scholar and SID were searched up to 1 October of 2010 for studies investigating Al-induced oxidant/antioxidant imbalance in humans or animals. The search terms were oxidant or antioxidant or oxidative stress and aluminium. The reference lists of articles were also reviewed for additional relevant studies.
Inclusion criteria: All of the Al-induced OS studies in human and
animal with key outcomes of change in oxidant/antioxidant imbalance parameters
Exclusion criteria: Reviews or letters and unpublished data such as thesis were excluded.
Human studies: Of publications in the initial database search, 10 trial
studies on the efficacy of Al on OS were reviewed. Information of these clinical
trials is summarized in the Table 1. The human studies showed
that Al has lately been implicated as one of the possible causal factors contributing
to neurodegenerative disorders according to OS potential of Al in the brain
(Bulat et al., 2008; Valentini
et al., 2007; Liao et al., 2006; Sargazi
et al., 2006; Bonnefont-Rousselot et al.,
2004; Anane and Creppy, 2001; Abou-Seif,
1998; Ongajooth et al., 1996). The relation
between Al toxicity and OS were studied in blood samples obtained from Al-exposed
workers (Ranjbar et al., 2008; Menevse
et al., 2006; Ferretti et al., 2003).
Also LPO was increased by exposure to Al in all of studies but data on SOD, CAT and GPx activity in exposure to Al are controversial. In half of studies, SOD, CAT and GPx activities were increased and in other half were reduced.
Animal studies: The details of the animal studies that investigated
OS effects of Al are summarized in Table 2. Twenty-five trials
on the efficacy of Al on OS were reviewed. The research results showed a significant
increase in LPO and inhibition of antioxidant enzymes by Al in plasma, liver,
brain, testes, kidney, renal cortex, biliary, serum, erythrocyte, hepatocyte,
intestine and sperm of Al-treated rabbits, rats and mice (Stevanovic
et al., 2009; Bhalla and Dhawan, 2009; Prakash
and Kumar, 2009; Sanchez-Iglesias et al., 2009;
Mahieu et al., 2009; Ranjbar
et al., 2008; Luo et al., 2007; Gonzalez
et al., 2007; Sharma et al., 2007;
Kutlubay et al., 2007; Albendea
et al., 2007; Abd-Elghaffar et al., 2005;
Nehru and Anand, 2005; Orihuela
et al., 2005; Abubakar et al., 2004;
El-Demerdash, 2004; Mahieu et
al., 2003; Zatta et al., 2002; Moumen
et al., 2001; Anane and Creppy, 2001; Amador
et al., 2001; Yoshino et al., 1999;
Katyal et al., 1997; Verstraeten
et al., 1997; Chainy et al., 1996;
Xie and Yokel, 1996; Julka and Gill,
1996; Oteiza et al., 1993; Fraga
et al., 1990).
|| Human studies considering the presence of oxidative stress
in aluminium exposure
|SOD: Superoxide dismutase, LPO: Lipid peroxidation, GSH: Glutathione,
GPX: Glutathione peroxidase, CAT: Catalase, GR: Glutathione reductase, G6PDH:
Glucose-6-phosphate dehydrogenase, TAP: Total antioxidant power, SH: Total
|| Animal studies considering the presence of oxidative stress
that induced by aluminium
|AChE: Acetylcholinesterase, SOD: Superoxide dismutase, LPO:
Lipid peroxidation, GSH: Glutathione, GPX: SH: Total thiol molecules, glutathione
peroxidase, CAT: Catalase, GR: Glutathione reductase, G6PDH: Glucose-6-phosphate
dehydrogenase, GST: Glutathione-S-teransferase, TAP: Total antioxidant power,
SH: Total thiol molecules, FR: Free radical, ROS: Reactive oxygen species
|| Antioxidants with protective effect on Al-induced oxidative
Data on the effect of Al on SOD are controversial. Studies indicated that CAT
and GPx activities in AL-treated animals are reduced. In brain, maximum LPO
was observed but it was not associated with alterations in antioxidant enzymes
Drugs used as antioxidants with protective effect on Al-induced OS are shown
in Table 3. In consideration of the strong evidence of OS
in Al exposure, antioxidant therapy deserves a place in protection against Al
toxicity (Kutlubay et al., 2007; Albendea
et al., 2007; Nehru et al., 2007;
Jyoti and Sharma, 2006; Sharma and
Mishra, 2006; Kowalczyk et al., 2005; Millan-Plano
et al., 2003; Swain and Chainy, 2000).
OS occurs when there is an excessive free radical production and/or low antioxidant
defense and results in chemical alterations of bio-molecules, which cause structural
and functional modifications (Massy and Khoa, 2002).
In response to OS, a great diversity of aldehydes are formed in biological system
that oxidize polyunsaturated fatty acids leading to LPO. Furthermore, these
aldehyde metabolites lower the body defense system especially by disturbance
of SOD (Esterbauer et al., 1991).
The brain is particularly vulnerable to oxidative damage, due to its high oxygen
consumption and high contents of easily oxidisable lipids and transition metal
ions, capable of catalyzing the formation of ROS (Bush,
2000). Brain tissue from patients with Alzheimers disease contains high
levels of LPO (Lovell et al., 1997; Sayre
et al., 1997) and protein oxidation products (Smith
et al., 1991). An association between LPO in the brain and CNS and
occurrence of some disease like Alzheimers has been reported (Xie
and Yokel, 1996).
Al seems to be transferred directly or after disruption of the Blood Brain
Barrier (BBB) to the brain. It seems that physiological ligands that present
at these barriers are altered in several disease states, thus result in an increased
Al exposure (Yokel, 2000). The pro-oxidant effects of
Al can damage the neuronal membrane by altering the physical properties of membrane,
interfering with the functioning of voltage-activated ionic channels or altering
the secretion of transmitters (Lebel and Bondy, 1991;
Donald et al., 1989). Al is not a transition
metal and therefore cannot initiate peroxidation but after binding to transferrin
reduces the binding of iron to its protein resulting in an increased concentration
of free iron in the intracellular stores. Studies have shown that this free
intracellular iron can cause the peroxidation of membrane lipids resulting in
membrane damage (Mousavi et al., 2010; Esterbauer
et al., 1991). However, this premise has been challenged because
Al may enhance Fe2+-dependent membrane LPO (Bondy
and Kirstein, 1996; Gutteridge et al., 1985).
Also, in vitro studies have indicated that Al greatly accelerates iron-mediated
LPO under acidic and neutral conditions (Xie and Yokel,
1996; Oteiza et al., 1993). LPO of biological
membranes results in the loss of membrane fluidity, changes in membrane potential,
increase in membrane permeability and alterations in receptor functions. A significant
increase in whole brain thiobarbituric acid reactive substances after stimulation
by Al salts has been reported (Julka and Gill, 1996).
Moreover, the amount of Al found in ferritin extracted from Alzheimers
disease brain samples was 5.6 times higher than that of ferritin from matched
control samples (Fleming and Josh, 1987). The increase
may have been due to a general increase in the availability of Al to the brain
of patients with Alzheimers disease and raised the possibility that Al
releases iron and Fe3+.
The increased LPO is, at least in part, due to an inhibition of SOD in the
brain. The result is a substantial increase in the rate of phospholipid peroxidation
in brain cells, leading to membrane damage and neuronal death. SOD presents
the first line of defense against superoxide, as it dismutases the superoxide
anion to H2O2 and O2. Because the SOD enzyme
generates H2O2, it works in collaboration with H2O2
removing enzymes. CAT converts H2O2 to water and oxygen.
CAT is present in the peroxisomes of mammalian cells and probably serves to
destroy H2O2 generated by oxidase enzymes located within
these subcellular organelles (Campbell et al., 1999;
Several experiments have shown that Al can affect glutathione (GSH) levels,
both in vivo and in vitro (El-Demerdash,
2004; Anderson, 1998). Inside the cell, more than
98% of GSH is found in the reduced form, supported by the activity of Glutathione-Reductase
(GR) which converts oxidized glutathione (GSSG) generated during OS, into the
reduced GSH (Wang and Ballatori, 1998; Anderson
et al., 1985). Glutathione-S-transferase (GST) performs an important
role in the detoxification of reactive metabolites catalyzing their conjugation
with GSH (Aw et al., 1991). Al might affect the
synthesis of GSH by decreasing the activity of GS, leading to a reduced GSH
content. Likewise, a slowing down in the GSH oxidized-to-reduced form by Al
could explain the increment in GSSG/GSH ratio. On the other hand, it has been
demonstrated that Al is able to inhibit NADPH-generating enzymes such as glucose
6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase (Zatta
et al., 2000). Since the reduced NADP is a main factor for the GSH
regeneration, the decreased GSH level could be ascribed to insufficient supply
Al has been shown to have a strong affinity for inorganic phosphate, citrate,
acetate, lactate, chloride, ATP, salicylates and many other ligands, but its
direct binding to thiol group is relatively weak (Martin,
1992). Al is also shown to inhibit Mg2+-ATPase activity. The
decrease in ATPase activity can result in inhibition of NADPH synthesis from
the glucose-6-phosphodehydrogenase system (Zaman et al.,
1990). This could result in the storage of GR substrate, i.e., NADPH, which
in turn might lower the reduction of oxidized GSH.
Cholinesterases are a large family of enzymatic proteins widely distributed
throughout both neuronal and non-neuronal tissues. In Alzheimers disease,
analytical as well as epidemiological studies suggest an implication of an abnormal
focal accumulation of Al in the brain. In Alzheimers disease, Al may interfere
with various biochemical processes including acetylcholine metabolism and can
thus act as a possible etiopathogenic cofactor. Acetylcholinesterase exists
in several molecular forms that differ in solubility and mode of membrane attachment
rather than in catalytic activity (Gholivand et al.,
2008, 2009). Kinetics measurement of acetylcholinesterase
activity in the absence and presence of Al has been reported, thus it can be
related to possible implication of Al in some neurodegeneration diseases.
There is evidence that Al may cause nuclear dissolution, chromosomal stickiness
and interference with DNA replication (Ezaki et al.,
2000; Martin, 1992). Studies on the gene expression
induced by Al treatments demonstrated that Al stress activates at least 30 general
stress genes (Hamilton et al., 2001). Some of
these genes encode antioxidant enzymes (e.g., glutathione-S-transferase, ascorbate
peroxidase, CAT and SOD) suggesting common mechanism induced by Al treatment
and OS (Rodriguez Milla et al., 2003; Hamilton
et al., 2001). However, this mechanism is not yet known and little
evidence for the formation of ROS during Al treatment has yet been documented
(Sivaguru et al., 2003).
Drugs used as antioxidants with protective effect on Al-induced OS are shown
in Table 3. For example it has been reported a partial protection
by vitamin E against Al-induced hepatotoxicity in the rat and rabbit (Yousef
et al., 2007; El-Demerdash, 2004). These
effects of vitamin E may be linked to its chain breaking antioxidant properties.
Also, vitamin E, a major lipid-soluble antioxidant belonging to tocopherol,
is the most effective chain breaking antioxidant within cell membrane. It is
able to repair oxidizing radicals directly, preventing the chain prop against
step during LPO (Yousef et al., 2007).
As a matter of fact, since OS is involved in the pathogenesis of many diseases
including inflammatory bowel diseases (Hosseini-Tabatabaei
and Abdollahi, 2008; Ghafari et al., 2006;
Jahanshahi et al., 2004), diabetes (Mohseni-Salehi-Monfared
et al., 2009a, b; Rahimi
et al., 2005, 2010; Radfar
et al., 2005; Afshari et al., 2004),
osteoporosis (Yousefzadeh et al., 2006) and other
oxidant-related diseases (Hasani-Ranjbar et al.,
2009, 2010; Vakilian et al.,
2009; Ranjbar et al., 2007; Rahimi
and Abdollahi, 2007; Malekirad et al., 2005),
so it would not be surprising to track roles of Al in other deliberating diseases
In conclusion the exact mechanism of Al toxicity is not yet known but accumulating evidences suggest this metal can potentiate oxidative and inflammatory events by activating ROS generation that eventually leads to tissue damage. Also, the effects of Al in manifestation of neurodisorders may arise from its interaction with the nervous system in various ways, which one of them is induction of oxidative damage through LPO of brain phospholipids.
This study is the outcome of an in-house non-financially supported study and authors declare no conflict of interest.
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