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 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
INTRODUCTION
of Plasmodium falciparium has also been shown to behepatotoxic (Nwanjo et al., 2007; Obi et al., 2004).
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., 1986; 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 Corresponding Author: 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., 1997). 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
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
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 Histological Study: 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: The chloroquine
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 DISCUSSION
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., 1994).
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., 1999). 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., 1996).
(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., 2009). 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., 2002; 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., 2002; environmental perturbation and departure from the normal Giordano, 2005; Murdoch et al., 2006), and other physiological conditions (Martins et al., 1978).
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 ACKNOWLEDGMENT
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., 2007).
University, Ekpoma for his technical assistance.
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