British Journal of Pharmacology and Toxicology 2(3): 97-103, 2011
ISSN: 2044-2467
© Maxwell Scientific Organization, 2011
Received: June 27, 2010
Accepted: July 04, 2010
Published: August 05, 2011
Effect of Chronic Oral Administration of Chloroquine on the Histology
of the Liver in Wistar Rats
1
A.M. Izunya,1A.O. Nwaopara, 1L.C. Anyanwu, 2M.A.C. Odike,
1
G.A. Oaikhena, 3J.K. Bankole and 4O. Okhiai
1
Department of Anatomy,
2
Department of Pathology,
3
Department of Medical Laboratory Sciences,
4
Department of Nursing Sciences, College of Medicine,
Ambrose Alli University, Ekpoma, Edo State, Nigeria
Abstract: The effect of chronic oral administration of chloroquine, an antimalarial and antirheumatic drug on
the histology of the liver in wistar rats was investigated. Ten wistar rats were randomly grouped into two,
control and treated. The treated group rats were administered 20 mg/kg body wt, weekly of chloroquine for
4 weeks while the control group rats were given distilled water for 4 weeks. On day 29th of the experiment,
the rats were weighed and sacrificed by cervical dislocation. The livers were carefully dissected out and quickly
fixed in 10% formal saline for histological studies. The histological findings after H and E methods indicated
that the treated sections of the liver showed cytoplasmic vacuolation; nuclear enlargement and vesiculation of
the hepatocytes when compared with the control. Thus, our result suggests that though chloroquine may be a
widely used antimalarial and antirheumatic drug, its chronic administration may have a deleterious effect on
the liver of wistar rats and by extension may affect its function. It is therefore recommended that the drug be
prescribed with caution in patients with history of liver disease.
Key words: Antimalarial, chloroquine, hepatotoxicity, histology, wistar rats
of Plasmodium falciparium has also been shown to be
hepatotoxic (Nwanjo et al., 2007; Obi et al., 2004).
Amongst the artemisinims, artesunate used as antimalarial
against multidrug- resistant strains of plasmodium
falciparum (Hien and White, 1993) has also been found to
be hepatotoxic (Ngokere et al., 2004; Nwanjo and Oze,
2007; Izunya et al., 2010).
Chloroquine is a widely used antimalarial agent
(Sharma and Mishra, 1999). In most endemic areas,
chloroquine use to be the main first line therapy for
malaria (Olanrewaju and Johnson, 2001) until recently
when WHO succeeded in promoting the combination
treatment for malaria infection (Nosten and Brasseur,
2002). It is also used to treat rheumatoid arthritis and
systemic lupus erytheromatosis (Ducharme and Farinotti,
1996; Dubois, 1978).
Availabe data show that chloroquine is concentrated
in the liver and many other tissues following its
administration (Adelusi and Salako, 1982). In toxic doses,
it is known to cause appreciable cellular damage to liver,
kidney and heart muscle (deGroot et al., 1981; Ngaha,
1982).
The liver is the largest solid organ in the body. It is
the centre of all metabolic activities in the body. Drugs
and other foreign substances are metabolized and
INTRODUCTION
A number of research studies have described the
deleterious effect of commonly prescribed anti-malarials
on the liver. Amodiaquine - formerly widely used as a
chemoprophylactic against Plasmodium spp. - produces
significant hepatocellular dysfunction (Larrey et al., 1986;
Neftel et al., 1986; WHO, 1990; Pero and Taylor, 2002;
Ajani et al., 2008), it is now rarely used due to a causative
association with bone-marrow depression (Cook, 1994).
'Fansidar' (pyrimethamine + sulphadoxine) has been
extensively used in chemoprophylaxis, and remains an
effective chemotherapeutic agent; it also produces
significant hepatocellular dysfunction (Reisinger et al.,
1989). Mefloquine, a compound now widely used both in
chemoprophylaxis and chemotherapy, can also produce
significant changes in liver-function tests (Reisinger et al.,
1989); it has not, however, been associated with
significant histological abnormality (Cook, 1994).
Quinine, again the first-line agent against P.falciparum
infection, is also hepatotoxic (Wernsdorfer and
McGregor, 1988; Okonkwo et al., 1997; Debra and
Megan, 1999), albeit rarely (Wernsdorfer and McGregor,
1988). Halofantrine which is widely prescribed for the
treatment of infections with chloroquine-resistant strains
Corresponding Author: Dr. Al-Hassan M. Izunya, Department of Anatomy, College of Medicine, Ambrose Alli University,
Ekpoma, Edo State, Nigeria
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Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
inactivated in the liver and is therefore susceptible to the
toxicity from these agents. Certain medicinal agents when
taken in overdoses and sometimes even when introduced
within therapeutic ranges may injure the liver.
Reports regarding the effects of chronic oral
administration of chloroquine on the histology of the liver
are scanty in existing literatures. There is however a
report which showed that chloroquine treatment for 12
weeks in mice causes cytolysis in hepatocytes (Okonkwo
et al., 1997).
This study was considered important since
rheumatoid arthritis and malaria are common ailments in
the tropics and the need to avoid the risk of hepatitis
resulting from prolonged oral administration of
chloroquine. In view of this, the present study was
carried out to investigate the effect of chronic oral
administration of chloroquine on the histology of the liver
in wistar rats.
Plate 1: (Control Group): Control section of the liver showing
normal histological features (Mag. X100)
MATERIALS AND METHODS
Location and duration of study: This study was
conducted at the histology laboratory of the College of
Medicine, Ambrose Alli University, Ekpoma, Edo State,
Nigeria. The preliminary studies, animal acclimatization,
drug procurement, actual animal experiment and
evaluation of results, lasted for a period of two months
(February and March, 2010). However, the actual
administration of the drug to the test animals lasted for
one month.
Animals: Experiments were carried out on ten (10)
Wistar rats (150 g) procured and maintained in the
Animal Holdings of the College of Medicine, Ambrose
Alli University, Ekpoma, Edo State, Nigeria. The animals
were housed under a controlled room temperature of
about 25-28ºC, relative humidity of about 60-80% and
photo-periodicity of 12 h day / 12 h night, and fed with
rat pellets (Bendel Feeds and Flour Mills, Ewu, Nigeria)
and water ad libitum. They were randomly assigned into
two groups, the control (n = 5) and treated (n = 5) groups.
Plate 2: (Experimental Group): Treatment section of the liver
that received 20mg/kg of chloroquine for 28 days,
showing cytoplasmic vacuolation (CV); nuclear
enlargement and vesiculation (NEV)(Mag. X400)
Histological Study: For light microscopic examination,
liver tissues from each groups were fixed with 10%
buffered formalin. The specimens were dehydrated in
ascending grades of ethanol, cleared in xylene and
embedded in paraffin wax. Sections of 5 :m in thickness
were prepared and stained with Haematoxylin and Eosin
(Drury et al., 1967) and then examined under light
microscopy. The photomicrographs of the relevant stained
sections were taken with the aid of a light microscope.
Drug preparation and administration: The chloroquine
phosphate tablets used for this experiment were
manufactured by Emzor Pharmaceutical Industries,
Lagos, Nigeria and certified by National Agency for Food
Drug Administration and Control (NAFDAC). They were
purchased from Irrua Specialist Teaching Hospital, Irrua,
Edo State, Nigeria. Rats in the treatment group received
20 mg/kg body weight of chloroquine phosphate
dissolved in distilled water weekly for 4 weeks. Rats in
the control group received equal volume of distilled water
using orogastric tube.
The animals were sacrificed using humane killing
with chloroform 24 h after the last dose on the 29th day
and the livers were harvested.
RESULTS
Histological analysis of the livers of rats in control
group showed normal morphological appearance
(Plate 1).
Histological analysis of the liver of rats in treated
group showed cytoplasmic vacuolation; nuclear
enlargement and vesiculation (Plate 2).
98
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
DISCUSSION
activities may be diminished or disrupted in sensitive
tissues (Oforah et al., 2004). Owing to its weak base
properties, chloroquine also accumulates in lysosomes
and may trigger apoptosis via the inhibition of autophagic
protein degradation (Amaravadi et al., 2007; Boya et al.,
2005; Fan et al., 2006; Shacka et al., 2006; Maclean
et al., 2008).
As an antimalarial, chloroquine acts by inhibiting
hemozoin biocrystallization, which gives rise to toxic free
heme accumulation that is responsible for the death of the
parasites (Barennes et al., 2006). Heme (iron
protoporphyrin IX) serves as the functional group of
various proteins, including hemoglobin, myoglobin, nitric
oxide synthase, and cytochromes (Beri and Chandra,
1993). Heme is therefore essential for diverse biologic
processes (Beri and Chandra, 1993).
It has however been shown that heme is a potentially
damaging species, which can directly attack and may
impair intracellular targets including the lipid bilayer, the
cytoskeleton, intermediary metabolic enzymes, and DNA
(Wagener et al., 2003). Moreover, excess of free heme
may constitute a major threat because heme catalyzes the
formation of ROS, resulting in oxidative stress and,
subsequently, cell injury (Kumar and Bandyopadhyay,
2005; Balla et al., 1991, 1993).
Interestingly, there are reports indicating that high
levels of free heme cause severe toxic effects to kidney,
liver, central nervous system and cardiac tissue (Kumar
and Bandyopadhyay, 2005; Dhalla et al., 1996).
Moreover, free heme is highly lipophilic and will rapidly
intercalate into the lipid membranes of adjacent cells
(Beri and Chandra, 1993), where it catalyzes the
formation of cytotoxic lipid peroxide via lipid
peroxidation and damages DNA through oxidative stress
(Kumar and Bandyopadhyay, 2005). Acworth et al.
(1997) revealed that increased lipid peroxidation can
negatively affect the membrane function by decreasing
membrane fluidity and changing the activity of membrane
bound enzymes and receptors.
ROS generation is a normal component of oxidative
phosphorylation and plays a role in normal redox control
of physiological signaling pathways (Sawyer et al., 2002;
Giordano, 2005; Murdoch et al., 2006). However,
excessive ROS generation triggers cell dysfunction, lipid
peroxidation, and DNA mutagenesis and can lead to
irreversible cell damage or death (Sawyer et al., 2002;
Giordano, 2005; Murdoch et al., 2006), and other
ROSmediated alterations in chromatin structure may
significantly affect gene expression (Konat, 2003;
Rahman, 2003). Modification of proteins by ROS can
cause inactivation of critical enzymes and can induce
denaturation that renders proteins nonfunctional
(Lockwood, 2000; Stadtman and Levine, 2003).
Moreover, there are also reports that cadmium toxicity in
Histological results suggested degeneration of the
liver cells of the wistar rats upon chronic oral
administration of chloroquine. This was shown by the
cytoplasmic vacuolation, nuclear enlargement and
vesiculation of the hepatocytes. The findings in this study
agree with the work of Okonkwo et al. (1997) in which
chloroquine administration for 12 weeks caused cytolysis
in hepatocytes in mice.
Degenerative changes have been reported to result in
cell death, which is of two types, namely apoptotic and
necrotic cell death (Cohen, 1993; Vaux et al., 1994).
These two types differ morphologically and biochemically
(Bose and Sinha, 1994). Apoptosis or Programmed Cell
Death (PCD) is a non-inflammatory response to tissue
damage characterized by a series of morphological and
biochemical changes (Sakkas et al., 1999; Sinha and
Swerdloff, 1999; Shen et al., 2002; Grunewald et al.,
2005). Apoptosis can be triggered in two principal ways:
by toxic chemicals or injury leading to damage of DNA or
of other important cellular targets, and activation or
inactivation of receptors by growth-regulating signal
factors in the organism (Schulte-Hermann et al., 1999).
Initiation of apoptosis can result from multiple
stimuli, including heat, toxins, Reactive Oxygen Species
(ROS), growth factor withdrawal, cytokines such as
transforming growth factor- beta, loss of matrix
attachment, glucocorticoid, nitric oxide, and radiation
(Thompson, 1995; Pollman et al., 1996). These stimuli
work in conjunction with other intrinsic factors that
determine the cell's potential to undergo apoptosis
(McConkey and Orrenius, 1991). However, high levels of
ROS disrupt the inner and outer mitochondrial
membranes, inducing the release of the cytochrome-C
protein and activating the caspase cascade which
ultimately results in the fragmentation of a cell's DNA
(Wyllie, 1980; Green, 1998; Makker et al., 2009).
Pathological or accidental cell death is regarded as
necrotic and could result from extrinsic insults to the cell
such as osmotic, thermal, toxic and traumatic effects
(Farber et al., 1981). The process of cellular necrosis
involves disruption of the membranes structural and
functional integrity. Cellular necrosis is not induced by
stimuli intrinsic to the cells as in apoptosis or
Programmed Cell Death (PCD), but by an abrupt
environmental perturbation and departure from the normal
physiological conditions (Martins et al., 1978).
Chloroquine is an aminoquinolinic membranepenetratable agent capable of intercalating into doublestranded DNA without causing physical damage to the
DNA (Mitscher, 2005). The DNA intercalation is nonselective for malarial parasites as it occurs also with
mammalian DNA. Thus protein synthesis and enzyme
99
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
ACKNOWLEDGMENT
liver may be mediated by the production of reactive
oxygen species known to induce necrosis in various rat
organs (Hsu et al., 2007; Razinger et al., 2008), lipid
peroxidation (Borges et al., 2008) and a decrease in
antioxidant enzymes (El-Sharaky et al., 2007).
ROS are small, oxygen-based molecules that are
highly reactive because of unpaired electrons (Papa and
Skulachev, 1997). ROS can react with cellular
components, especially membrane lipids, and lead to cell
damage (Rikans and Hornbrook,1997). The most
prominent ROS are the superoxide anion (O2•–), hydrogen
peroxide (H2O2), and the hydroxyl ion (OH•) (Turner and
Lysiak, 2008). Cells also have intrinsic antioxidant
systems that counter ROS accumulation. These include
enzymes such as catalase, glutathione peroxidases, and
superoxide dismutase, and nonenzymatic antioxidants,
such as vitamins E, C, beta carotene, ubiquinone, lipotic
acid, and urate (Nordberg and Arner, 2001; Giordano,
2005).
In a normal liver, the level of ROS is low, and
antioxidant defenses are adequate to protect the liver from
oxidative damage (Fernandez et al., 1997). Nevertheless,
under several situations, the rate of generation of ROS
exceeds that of their removal and oxidative stress occurs
(Giordano, 2005; Di Giulio et al., 1995; Halliwell and
Gutteridge, 1999; Livingstone, 2001). However, more
severe oxidative stress can cause cell death and even
moderate oxidation can trigger apoptosis, while more
intense stresses may cause necrosis (Lennon et al., 1991).
However, under the severe levels of oxidative stress that
cause necrosis, the damage causes ATP depletion,
preventing controlled apoptotic death and causing the cell
to simply fall apart (Lelli et al., 1998; Lee et al., 1999).
In this study, chloroquine may have acted directly
through generation of high levels of free heme or ROS on
the hepatocytes, affecting their cellular integrity and
causing defect in membrane permeability and cell volume
homeostasis. In cellular necrosis, the rate of progression
depends on the severity of the environmental insults. The
greater the severity of the insults the more rapid the
progression of neuronal injury (Ito et al., 2003). The
principle holds true for toxicological insult to the brain
and other organs (Martins et al., 1978). Thus, it may be
inferred from this result that chronic oral administration
of chloroquine is toxic to the liver in wistar rats.
The authors thank Mr Charles Idehen of Histology
Laboratory of the College of Medicine Ambrose Alli
University, Ekpoma for his technical assistance.
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