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Iranian Journal of
Medical Hypotheses and Ideas
Original article
Application of garlic organosulfur compounds in prevention of cyclosporine
A-induced hepatotoxicity
Yadollah Shakiba 1*, 2, Ali Mostafaie 2, Delnia Arshadi 2 and Behnam Sabayan 3
Address:
1
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
3
Shiraz University of Medical Sciences, Student Research Center, Zand Avenue, Central Building, Shiraz, Fars
2
Corresponding author:
Yadollah Shakiba (MD), Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
E-mail: [email protected]
Telefax: +98-831-4276471
Postal zip code: 6714869914
Received: 23 Oct 2008
Accepted: 21 Dec 2008
Published: 3 Jan 2009
Iran J Med Hypotheses Ideas, 2009, 3:3
© 2009 Yadollah Shakiba, Ali Mostafaie, Delnia Arshadi and Behnam Sabayan; licensee Tehran Univ. Med. Sci.
Abstract
Cyclosporine A (CsA) is a powerful immunosuppressant drug most widely used in management
of organ transplantation and autoimmune diseases. However, in therapeutic doses CsA induces
several side effects including renal and liver toxicity. CsA induced hepatotoxicity usually occurs
in the first 90 post-transplant days and can limit its therapeutic use. Cumulative data showed
that oxidative stress induced by reactive oxygen species (ROS) over production and
compromised antioxidant capacity play an important role in the development of hepatotoxicity
in CsA treated patients. CsA induced oxidative stress decreases hepatocyte reduced glutathione
(GSH) and impairs the function of its related enzymes. Consequently any mechanism which
removes ROS or prevents hepatic GSH depletion or induce production of GSH dependent
enzymes may provide protection for hepatotoxicity in CsA-treated patient. Garlic organosulfur
compounds have been reported that enhance cellular antioxidant activity by radical scavenging
abilities and augmentation of endogenous antioxidants via prevention of GSH depletion and
increasing of GSH dependent enzymes activity and their gene expression. Based on these facts
we propose the hypothesis that garlic organosulfur compounds can prevent CsA hepatotoxicity.
Before clinical use further investigations in animal models are needed.
Keywords
Cyclosporine,Hepatotoxicity,Garlic, Oxidative stress
Introduction
Cyclosporine A (CsA), a fungal polypeptide,
was first identified in 1976 as a novel antibiotic.
CsA is now marked as a frequently used
immunosuppressive agent in transplant medicine
to prevent graft rejection. CsA significantly
improves graft survival following renal, cardiac,
pancreatic, bone marrow and liver transplantation
(1). In fact, after introducing cyclosporine to
Irn J Med Hypotheses Ideas 2009, 3:3
Yadollah Shakiba, Ali Mostafaie, Delnia Arshadi and
Behnam Sabayan
transplant medicine, survival of transplanted
organs increased considerably to more than 80% at
2 years post transplantation. Today, a large number
of transplanted patients receive cyclosporine as a
crucial immunosuppressant drug (2).
In addition this drug is used in the treatment
of wide spectrum of autoimmune diseases such as
uveitis, rheumatoid arthritis, psoriasis, nephritic
syndrome, inflammatory bowel disease and
primary biliary cirrhosis (1). However CsA has
also side effects including renal, hepatic, cardiac
and neural toxicity, among which, hepatotoxicity
is also one of the most disquieting side
effects. It has been reported that impaired hepatic
function occurs in 20 to 50% of CsA treated
patients (2). Cholestasis, hyperbilirubinemia,
hypoproteinemia, increased alkaline phosphatase,
elevated transaminases, inhibition of protein
synthesis and disturbed lipid secretion in both
human and experimental animals was found to
characterize CsA-induced
hepatotoxicity (3).
Hepatotoxicity usually occurs in the first 90 posttransplant days and can limit CsA clinical
application (4).
Discussion
The Hypotheses
Although the exact mechanism of CsAinduced hepatotoxicity is not completely
understood, numerous current findings suggest that
oxidative stress mechanism playing an important
role in its pathology. CsA therapy induces
overproduction of reactive oxygen species (ROS)
in hepatocytes and lowers their antioxidant
capacity. Based on this fact, we herein offer a
hypothesis that ingestion of potentially antioxidant
garlic organosulfur compounds may be useful in
prevention of CsA-induced hepatotoxicity.
Evaluation of the hypotheses
To test this hypothesis we offer following
methods:
1- Oral or intraperitoneal administration of
garlic organosulfur compounds to animals before
and during of treatment with CsA and evaluation
of oxidative stress markers in their serum and liver
tissue in comparison to control group.
2- Simultaneous addition of garlic organosulfur compounds and CsA to cultured rat
hepatocytes and evaluation of toxicity and lipid
peroxidation in comparison to addition of CsA in
control plates.
3- Moreover since garlic is a safe food for
human and in normal doses has no toxicity, it is
possible that we test this hypothesis in
cyclosporine treated patients.
CsA and oxidative stress in hepatocytes
As noted above, the mechanism underlying
CsA hepatotoxicity is not completely cleared but
cumulative data showed that oxidative stress plays
an important role in its toxicity. For example Wolf
et al. reported that in primary rat hepatocyte
culture, CsA increases reactive oxygen species
(ROS) and malondialdehyde (MDA) production
that are hallmarks of oxidative stress (5). In other
research it has been showed that oral administration of CsA to rabbit increases MDA level and
catalase (CAT) activity in liver preparations of
rabbits. Increased CAT activity is a compensatory
mechanism against high hydrogen peroxide
production and confirms CsA induced oxidative
stress in hepatocytes (6). Cell membrane is one of
the most susceptible sites to ROS. Free radicals
react with polyunsaturated fatty acids and form
lipid peroxides. Damage to Cell membrane via
lipid peroxidation can impair its fluidity and
elasticity permanently which can lead to rupture of
the cell (7).
New findings revealed that GSH depletion is
another important mechanism of CsA hepatotoxicity. GSH is an important cellular antioxidant
defense system against free radical overproduction
and decreasing of its cellular concentration impairs
cellular defense against oxidative stress (8). The
depletion of GSH in the hepatocytes makes them
susceptible to the oxidative stress. In previous
researches it has been reported that CsA ingestion
leads to a meaningful decrease in hepatic reduced
glutathione GSH content. For example, Jimenez et
al. found that total amount of hepatocytes
glutathione significantly decreased in rats treated
with CsA. In addition they notified that CsA
increases oxidized glutathione concentrations
which can modulate the activity of various
regulatory enzymes and might be a cause of the
impaired hepatocellular functions induced by CsA
(9). In another study Inselmann et al. reported that
CsA-induced hepatotoxicity was exacerbated by
glutathione depletion (10). Based on these data we
can imagine that any mechanism which removes
ROS production and GSH depletion or induces
production of GSH dependent enzymes may be
useful for protection of hepatotoxicity in CsAtreated patients.
The CsA oxidative stress mechanism in
hepatocytes confirmed by other studies that
showed antioxidant can prevent CsA-induced
hepatotoxicity. Numerous studies obviously
showed that antioxidants such as α-tocopherol,
vitamin C and E, taurine, N-acetylcysteine and
melatonin can protect hepatocytes against CsA
toxicity in rat hepatocyte cultures (11-16).
Page 2 of 4 (page number not for citation purposes) Irn J Med Hypotheses Ideas 2009, 3:3
Yadollah Shakiba, Ali Mostafaie, Delnia Arshadi and
Behnam Sabayan
Garlic
organosulfur
compounds
and
antioxidant properties
The postulated role of garlic organosulfur
compounds in prevention of CsA hepatotoxicity
can be explained by 1) their ability in free radical
scavenging 2) prevention of hepatocyte GSH
depletion.
The role of garlic organosulfur compounds in
free radical scavenging has been investigated by
numerous investigations. Several studies obviously
showed antioxidant activity of garlic compositions
against oxidative stress in tissues (17-19). Allicin
is a major component of garlic organosulfurs and
its antioxidant properties confirmed by many
investigations (17-19). In addition to allicin other
garlic organosulfurs like alliin, allyl cysteine, allyl
disulfide, represent antioxidant properties and can
neutralize several types of ROS (20). Moreover
garlic organosulfurs absorb from gastrointestinal
system to circulation and can effect on body
organs effectively. The bioavailability of these
organosulfurs can be estimated by assaying
expiration allyl methyl sulfide content (21).
Many previous researches and investigations
showed that garlic organosulfur compounds
prevent hepatotoxicity induced by isoniazid and
rifampicin (22), galactosamine/endotoxin (23),
Carbon tetrachloride (24) and naphthalene (25) in
hepatocyte. The mechanism of induced liver
toxicity by these drugs is similar. All of them
induce oxidative stress in hepatocytes.
Augmentation of glutathione and its related
enzymes, cellular antioxidant defense systems, is
another major mechanism of garlic organosulfur
hepatoprotection. Garlic prevents cells against
GSH depletion and activates GSH dependent
enzymes gene expression (26-29).
As mentioned above, nephrotoxicity is another
major adverse effect of CsA. It has been reported
that CsA induces renal and liver toxicity by a
similar mechanism. CsA induced renal damage is
accompanied by increase in reactive oxygen
species, lipid peroxidation and decrease in
expression and activity of antioxidant enzymes
like superoxide dismutase, catalase, and
glutathione peroxidase (30-31). Some recent
investigations indicated that garlic organosulfurs
attenuate CsA nephrotoxicity and protect renal
tubules from CsA induced oxidative stress (32). In
a recent study Durak et al. reported that orally
ingestion of garlic decreases MDA production in
kidney of cyclosporine treated rats by antioxidant
activities (33). In an interesting clinical study
jabbari et al. reported that garlic ingestion
decreases cyclosporine induced oxidative stress in
renal transplanted patients (34).
As we know in comparision to other antioxidant agents, garlic is a safe, available, popular food
and in normal doses has no side effect in almost all
of people. Moreover garlic is a chip food and can
be cost effective antioxidant agent for patients. We
think that after confirming this hypothesis by in
vitro and in view studies, garlic can be used widely
in cyclosporine treated patients as a part of their
food regime and can help them to tolerate
therapeutic doses of cyclosporine.
Conclusion
Taken together, these data indicate the pivotal
role of oxidative stress in CsA hepatotoxicity.
Consequently any mechanisms which decrease
oxidative stress may limit the hepatotoxicity
associated with CsA. Therefore, we hypothesized
that garlic organosulfur may be effective in CsAinduced hepatotoxicity treatment. Clinical
investigation on animal models can give us more
clear clues in this regard.
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