Effect of chronic oral administration of chloroquine on the histology of the liver in wist
British Journal of Pharmacology and Toxicology 2(3): 97-103, 2011ISSN: 2044-2467 Maxwell Scientific Organization, 2011Received: June 27, 2010
Effect of Chronic Oral Administration of Chloroquine on the Histology
of the Liver in Wistar Rats
1A.M. Izunya,1A.O. Nwaopara, 1L.C. Anyanwu, 2M.A.C. Odike,
1G.A. Oaikhena, 3J.K. Bankole and 4O. Okhiai
3Department of Medical Laboratory Sciences,
4Department of Nursing Sciences, College of Medicine,
Ambrose Alli University, Ekpoma, Edo State, Nigeria
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.
Antimalarial, chloroquine, hepatotoxicity, histology, wistar rats
of Plasmodium falciparium has also been shown to behepatotoxic (Nwanjo et al
., 2007; Obi et al
A number of research studies have described the
Amongst the artemisinims, artesunate used as antimalarial
deleterious effect of commonly prescribed anti-malarials
against multidrug- resistant strains of plasmodium
on the liver. Amodiaquine - formerly widely used as a
falciparum (Hien and White, 1993) has also been found to
chemoprophylactic against Plasmodium
spp. - produces
be hepatotoxic (Ngokere et al
., 2004; Nwanjo and Oze,
significant hepatocellular dysfunction (Larrey et al
Neftel et al
., 1986; WHO, 1990; Pero and Taylor, 2002;
Chloroquine is a widely used antimalarial agent
Ajani et al
., 2008), it is now rarely used due to a causative
(Sharma and Mishra, 1999). In most endemic areas,
association with bone-marrow depression (Cook, 1994).
chloroquine use to be the main first line therapy for
'Fansidar' (pyrimethamine + sulphadoxine) has been
malaria (Olanrewaju and Johnson, 2001) until recently
extensively used in chemoprophylaxis, and remains an
when WHO succeeded in promoting the combination
effective chemotherapeutic agent; it also produces
treatment for malaria infection (Nosten and Brasseur,
significant hepatocellular dysfunction (Reisinger et al
2002). It is also used to treat rheumatoid arthritis and
1989). Mefloquine, a compound now widely used both in
systemic lupus erytheromatosis (Ducharme and Farinotti,
chemoprophylaxis and chemotherapy, can also produce
significant changes in liver-function tests (Reisinger et al
Availabe data show that chloroquine is concentrated
1989); it has not, however, been associated with
in the liver and many other tissues following its
significant histological abnormality (Cook, 1994).
administration (Adelusi and Salako, 1982). In toxic doses,
Quinine, again the first-line agent against P.falciparum
it is known to cause appreciable cellular damage to liver,
infection, is also hepatotoxic (Wernsdorfer and
kidney and heart muscle (deGroot et al
., 1981; Ngaha,
McGregor, 1988; Okonkwo et al
., 1997; Debra and
Megan, 1999), albeit rarely (Wernsdorfer and McGregor,
The liver is the largest solid organ in the body. It is
1988). Halofantrine which is widely prescribed for the
the centre of all metabolic activities in the body. Drugs
treatment of infections with chloroquine-resistant strains
and other foreign substances are metabolized and
Dr. Al-Hassan M. Izunya, Department of Anatomy, College of Medicine, Ambrose Alli University,
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
inactivated in the liver and is therefore susceptible to thetoxicity from these agents. Certain medicinal agents whentaken in overdoses and sometimes even when introducedwithin therapeutic ranges may injure the liver.
Reports regarding the effects of chronic oral
administration of chloroquine on the histology of the liverare scanty in existing literatures. There is however areport which showed that chloroquine treatment for 12weeks in mice causes cytolysis in hepatocytes (Okonkwoet al
This study was considered important since
rheumatoid arthritis and malaria are common ailments inthe tropics and the need to avoid the risk of hepatitisresulting from prolonged oral administration ofchloroquine. In view of this, the present study wascarried out to investigate the effect of chronic oral
Plate 1: (Control Group): Control section of the liver showing
administration of chloroquine on the histology of the liver
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
Experiments were carried out on ten (10)
Wistar rats (150 g) procured and maintained in the
Animal Holdings of the College of Medicine, Ambrose
Plate 2: (Experimental Group): Treatment section of the liver
that received 20mg/kg of chloroquine for 28 days,
Alli University, Ekpoma, Edo State, Nigeria. The animals
showing cytoplasmic vacuolation (CV); nuclear
were housed under a controlled room temperature of
enlargement and vesiculation (NEV)(Mag. X400)
about 25-28ºC, relative humidity of about 60-80% andphoto-periodicity of 12 h day / 12 h night, and fed with
For light microscopic examination,
rat pellets (Bendel Feeds and Flour Mills, Ewu, Nigeria)
liver tissues from each groups were fixed with 10%
and water ad libitum. They were randomly assigned into
buffered formalin. The specimens were dehydrated in
two groups, the control (n = 5) and treated (n = 5) groups.
ascending grades of ethanol, cleared in xylene andembedded in paraffin wax. Sections of 5 :m in thickness
Drug preparation and administration:
were prepared and stained with Haematoxylin and Eosin
phosphate tablets used for this experiment were
(Drury et al
., 1967) and then examined under light
manufactured by Emzor Pharmaceutical Industries,
microscopy. The photomicrographs of the relevant stained
Lagos, Nigeria and certified by National Agency for Food
sections were taken with the aid of a light microscope.
Drug Administration and Control (NAFDAC). They werepurchased from Irrua Specialist Teaching Hospital, Irrua,Edo State, Nigeria. Rats in the treatment group received
20 mg/kg body weight of chloroquine phosphatedissolved in distilled water weekly for 4 weeks. Rats in
Histological analysis of the livers of rats in control
the control group received equal volume of distilled water
group showed normal morphological appearance
The animals were sacrificed using humane killing
Histological analysis of the liver of rats in treated
with chloroform 24 h after the last dose on the 29th day
group showed cytoplasmic vacuolation; nuclear
enlargement and vesiculation (Plate 2).
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
activities may be diminished or disrupted in sensitivetissues (Oforah et al
., 2004). Owing to its weak base
Histological results suggested degeneration of the
properties, chloroquine also accumulates in lysosomes
liver cells of the wistar rats upon chronic oral
and may trigger apoptosis via the inhibition of autophagic
administration of chloroquine. This was shown by the
protein degradation (Amaravadi et al
., 2007; Boya et al
cytoplasmic vacuolation, nuclear enlargement and
2005; Fan et al
., 2006; Shacka et al
., 2006; Maclean
vesiculation of the hepatocytes. The findings in this study
agree with the work of Okonkwo et al
. (1997) in which
As an antimalarial, chloroquine acts by inhibiting
chloroquine administration for 12 weeks caused cytolysis
hemozoin biocrystallization, which gives rise to toxic free
heme accumulation that is responsible for the death of the
Degenerative changes have been reported to result in
parasites (Barennes et al
., 2006). Heme (iron
cell death, which is of two types, namely apoptotic and
protoporphyrin IX) serves as the functional group of
necrotic cell death (Cohen, 1993; Vaux et al
various proteins, including hemoglobin, myoglobin, nitric
These two types differ morphologically and biochemically
oxide synthase, and cytochromes (Beri and Chandra,
(Bose and Sinha, 1994). Apoptosis or Programmed Cell
1993). Heme is therefore essential for diverse biologic
Death (PCD) is a non-inflammatory response to tissue
damage characterized by a series of morphological and
It has however been shown that heme is a potentially
biochemical changes (Sakkas et al
., 1999; Sinha and
damaging species, which can directly attack and may
Swerdloff, 1999; Shen et al
., 2002; Grunewald et al
impair intracellular targets including the lipid bilayer, the
2005). Apoptosis can be triggered in two principal ways:
cytoskeleton, intermediary metabolic enzymes, and DNA
by toxic chemicals or injury leading to damage of DNA or
(Wagener et al
., 2003). Moreover, excess of free heme
of other important cellular targets, and activation or
may constitute a major threat because heme catalyzes the
inactivation of receptors by growth-regulating signal
formation of ROS, resulting in oxidative stress and,
factors in the organism (Schulte-Hermann et al
subsequently, cell injury (Kumar and Bandyopadhyay,
Initiation of apoptosis can result from multiple
stimuli, including heat, toxins, Reactive Oxygen Species
Interestingly, there are reports indicating that high
(ROS), growth factor withdrawal, cytokines such as
levels of free heme cause severe toxic effects to kidney,
transforming growth factor- beta, loss of matrix
liver, central nervous system and cardiac tissue (Kumar
attachment, glucocorticoid, nitric oxide, and radiation
and Bandyopadhyay, 2005; Dhalla et al
(Thompson, 1995; Pollman et al
., 1996). These stimuli
Moreover, free heme is highly lipophilic and will rapidly
work in conjunction with other intrinsic factors that
intercalate into the lipid membranes of adjacent cells
determine the cell's potential to undergo apoptosis
(Beri and Chandra, 1993), where it catalyzes the
(McConkey and Orrenius, 1991). However, high levels of
formation of cytotoxic lipid peroxide via lipid
ROS disrupt the inner and outer mitochondrial
peroxidation and damages DNA through oxidative stress
membranes, inducing the release of the cytochrome-C
(Kumar and Bandyopadhyay, 2005). Acworth et al
protein and activating the caspase cascade which
(1997) revealed that increased lipid peroxidation can
ultimately results in the fragmentation of a cell's DNA
negatively affect the membrane function by decreasing
(Wyllie, 1980; Green, 1998; Makker et al
membrane fluidity and changing the activity of membrane
Pathological or accidental cell death is regarded as
necrotic and could result from extrinsic insults to the cell
ROS generation is a normal component of oxidative
such as osmotic, thermal, toxic and traumatic effects
phosphorylation and plays a role in normal redox control
(Farber et al
., 1981). The process of cellular necrosis
of physiological signaling pathways (Sawyer et al
involves disruption of the membranes structural and
Giordano, 2005; Murdoch et al
., 2006). However,
functional integrity. Cellular necrosis is not induced by
excessive ROS generation triggers cell dysfunction, lipid
stimuli intrinsic to the cells as in apoptosis or
peroxidation, and DNA mutagenesis and can lead to
Programmed Cell Death (PCD), but by an abrupt
irreversible cell damage or death (Sawyer et al
environmental perturbation and departure from the normal
Giordano, 2005; Murdoch et al
., 2006), and other
physiological conditions (Martins et al
ROSmediated alterations in chromatin structure may
Chloroquine is an aminoquinolinic membrane-
significantly affect gene expression (Konat, 2003;
penetratable agent capable of intercalating into double-
Rahman, 2003). Modification of proteins by ROS can
stranded DNA without causing physical damage to the
cause inactivation of critical enzymes and can induce
DNA (Mitscher, 2005). The DNA intercalation is non-
denaturation that renders proteins nonfunctional
selective for malarial parasites as it occurs also with
(Lockwood, 2000; Stadtman and Levine, 2003).
mammalian DNA. Thus protein synthesis and enzyme
Moreover, there are also reports that cadmium toxicity in
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011
liver may be mediated by the production of reactive
oxygen species known to induce necrosis in various ratorgans (Hsu et al
., 2007; Razinger et al
., 2008), lipid
The authors thank Mr Charles Idehen of Histology
peroxidation (Borges et al
., 2008) and a decrease in
Laboratory of the College of Medicine Ambrose Alli
antioxidant enzymes (El-Sharaky et al
University, Ekpoma for his technical assistance.
ROS are small, oxygen-based molecules that are
highly reactive because of unpaired electrons (Papa and
Skulachev, 1997). ROS can react with cellularcomponents, especially membrane lipids, and lead to cell
Acworth, I.N., D.R. McCabe and T. Maber, 1997. The
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Adelusi, S.A. and L.A. Salako, 1982. Tissue and blood
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Chapter 2. Empiric Therapy: CNS Infections Encephalitis Usual Pathogens IV-to-PO Switch Acyclovir 10 mg/kg (IV) q8h x 7 days, then if able to take oralmedications, complete 14-21 days of total therapy withacyclovir 400 mg (PO) 5x/day or valacyclovir 1 gm (PO) q8h or famciclovir 500 mg (PO) q8hUsual PathogensCalifornia encephalitis (CE), Western equine encephalitis (WEE), Venezuelan e