Hepatotoxicity and Nephrotoxicity Studies of Ethanol Extracts of Annona Muricata Leaves and Fagara Zanthoxyloide Roots on Zidovudine-Induced Wistar Rats

Hepatotoxicity and Nephrotoxicity Studies of Ethanol Extracts of Annona Muricata Leaves and Fagara Zanthoxyloide Roots on Zidovudine-Induced Wistar Rats
Hepatotoxicity and Nephrotoxicity Studies of Ethanol Extracts
of Annona Muricata Leaves and Fagara Zanthoxyloide Roots
on Zidovudine-Induced Wistar Rats
*Ekere, O.U.1, Ogunka-Nnoka, C.U. 2, Monago-Ighorodje, C.C.3
1,2,3Department of Biochemistry, University of Port Harcourt, Choba, Port Harcourt, River State, Nigeria.
The study determined the effects of administration of ethanol extracts of Annona muricata leaves
(AML) and Fagara zanthoxyloide roots (FZR) on liver and kidney indices in zidovudine (ZDV)-
induced Wistar rats. Animals were grouped into five (5); group 1 served as normal control, groups
2-5 were induced with 100g/mlZDV/Kgbw and group 3 treated with 35IU/Kgbw of erythropoietin,
group 4 with 4.5g/mlAML/Kgbw and group 5 with 3.8g/mlFZR/Kgbw for six weeks. Serum liver
enzymes, other biochemicals (total protein, albumin, globulin, bilirubin, urea and creatinine),
organ weights and histological examination were used to assess the impact on the liver and
kidney using standard methods. A significant elevation (p≤0.05) in the activities of serum liver
enzymes and bilirubin accompanied by a significant decrease (p≤0.05) in the other biochemicals
were observed in group 2. Treatment with extracts resulted in a modulation of the induced effects
of ZDV causing a significant decrease in the serum liver enzymes, bilirubin and increase in the
total protein, albumin and globulin concentrations. Histology of the liver showed altered
architecture, blood vessel congestion and necrosis; while the kidneys were hypoplastic with
signs of swelling (group 2) which was gradually reverted on treatment with extracts. The study
suggests that extracts of AML and FZR may confer some degree of protection to the liver and
kidney.
Keywords: Annona muricata, Fagara zanthoxyloide, zidovudine, hepatotoxicity, nephrotoxicity, Wistar rat
INTRODUCTION
Plants are fast becoming an important source of life-saving
medications for individuals with several symptoms or
ailments.The preference and increasing interest given to
traditional system of medicine over synthetic/orthodox
medication has spurred research into the toxicological
impact of these plants with regards to hepatotoxicity and
nephrotoxicity as these organs serve as initial contact
points for chemicals and toxins as they enter and as they
are excreted from the body. The liver as a vital organ, is
involved in the metabolism of drugs and exogenous
compounds, breakdown of nutrients, the buildup of body
tissues, storage sites for vitamins and minerals and
elimination of toxins (Adisa et al., 2014). The kidneys are
involved in the removal of waste products, re-absorption of
nutrients and maintaining electrolyte concentrations in the
body etc. As these two organs are of great importance for
biotransformation (liver) and the subsequent excretion
(kidney) an impairment in their function would adversely
affect their health status (Belonwu et al., 2013). The
degree of impairment may be measured by the activities of
several liver enzymes in serum dislodged as a result of
damage to the liver or by a measure of the concentration
of certain biochemical compounds (bilirubin, creatinine,
urea) in the blood produced by or expected to be bio-
transformed by the liver and excreted by the kidney (Adisa
et al., 2014).
*Corresponding Author: Ekere Oghenekaro
Uchechukwu, Department of Biochemistry, University of
Port Harcourt, Choba, Port Harcourt, River State, Nigeria.
Email: Oghenekarouche@gmail.com
Research Article
Vol. 4(1), pp. 045-053, July, 2019. © www.premierpublishers.org, ISSN: 1822-424X
International Journal of Toxicology and Environmental Health

Ekere et al. 046
Annona muricata (AM) commonly called soursop in
Nigeria is widely distributed in the tropical regions of West-
Africa. The leaves, barks, fruits and seeds have been
recorded to possess several medicinal applications
(Badrie and Schauss, 2009). The leaves have been
applied or ingested as decoctions in cases of mild pains
and also used in the treatment of symptoms associated
with cold and asthma (Coria-Tellez et al., 2018). The barks
and seeds have been used in the treatment of
hypertension, diabetes, bacterial infections, inflammatory
diseases and cancer (Ezurike and Prieto, 2014; De souza
et al., 2011). They are reported to be rich in alkaloids,
phenols, essential oils, acetogenins, carbohydrates, fiber
and other compounds (Ekere et al., 2019).
Fagara zanthoxyloide (FZ) is a plant common to the rain
forests of Southern Nigeria. The leaves have been
reported to contain alkaloids, steroids, lignans and
carbohydrates (Ekere et al., 2019). The most common
traditional application is in the treatment of toothaches,
urinary and venereal disease. It has also been used as
components of antiseptics, anti-parasitic, anti-
hypertensive, anti-inflammatory and analgesics
(Adefisoye et al., 2012; Ogwal-Okeng et al., 2003). The
most important discovery on the roots of Fagara
zanthoxyloide is their proposed use as an anti-sickling
agent due to the activity of 2-hydroxylmethy benzoic acid
(a bio-component of the root extract) on the red cell
membrane and preservation of the colour of the blood.
Zidovudine is a nucleoside reverse transcriptase inhibitor
initially applied in the treatment of cancer and currently
being used as part of highly active antiretroviral therapy
(Ekere and Ikpeama, 2019; Peters et al., 2014). It has
been linked with several side effects such as anaemia, loss
of appetite, weight loss, leucopenia, oxidative stress,
thrompocytopenia, nausea, vomiting and shortness of
breath etc. The culmination of these effects and the
important role this drug plays in the maintenance of health
in conditions of immunodeficiency has spurred research
into tackling the side effects of this drug.
The saying that health is wealth is one that has been said
one too many in Nigeria. The management of the health
status in rural areas in Nigeria is plagued by the
occurrence of several side effects which according to
medical practitioners interviewed ranged from appetite
loss, weight loss, immune suppression, anaemia etc. In
lieu to curb mitigating side effect, several rural dwellers
indulge in the consumption of several tradio-medical
concoctions. Several plants are acclaimed to be wonder-
working by traditional medicine dispensers in South-
southern Nigeria and include Annona muricata and Fagara
zanthoxyloide. This study aims at evaluating and providing
insights into the long-term toxicological impacts of the
extracts of these plants on the liver and kidney in cases of
possible side effects induced by zidovudine in Wistar rats
(Ekere and Ikpema, 2019; Ekere et al., 2019, Peters et al.,
2014).
MATERIALS AND METHOD
Collection of plant materials
Annona muricata leaves (AML) and Fagara zanthoxyloide
roots (FZR) were obtained from Alakahia, Obio/Akpor
L.G.A, Rivers State, Nigeria. The plant materials were
identified by Dr. B. Chikezie of the Plant Science and
Biotechnology Department, University of Port-Harcourt.
Preparation of plant materials
The AML and FZR collected were sterilized with a stream
of distilled water and left to air dry at 25˚C. They were
pulverized with a mechanical grinder until a uniform coarse
powder is obtained for each.
Extraction of plant materials
The dried powdered materials (300g) were placed in a
conical flask and extracted using 3 litres of absolute
ethanol for 1 week. The mixture was centrifuged and
filtered. The residue was evaporated to dryness and stored
at 4°C in a refrigerator.
Animal Experimental treatments
Seventy (70) albino rats weighing (200-250g) were
purchased from the animal house of the Department of
Biochemistry, University of Port Harcourt, Rivers State,
Nigeria and divided into five groups of 15 rats each; and
housed in Griffin and George modular cage system
Group 1: Served as the normal control group which
received only water and normal feed
Group 2: Served as the negative control group which
received 100mg/ml of ZDV/Kg bw
Group 3: Served as the positive control which received
35IU EPO/Kg bw
Group 4: Received 100mg/ml ZDV/Kg bw and
4.5g/mlAML/Kg bw
Group 5: Received 100mg/ml ZDV/Kg bw and
3.8g/mlFZR/Kg bw
METHODS
Zidovudine (ZDV) was administered for two weeks in
groups 2-5, prior to experimental treatment with extracts
while treatment with extracts was performed for a period of
6 weeks. Twenty-four (24) hours after termination of
experimentation, the animals were weighed and
anaesthetized in chloroform. Blood samples were
collected into heparinized bottles from the jugular vein and
centrifuged at 500 rpm for 12 minutes to obtain the serum.
The liver and kidney were also excised after dissection;
with the variations in body and organ weights determined
by the method described by Akinnawo et al., (2005).

Int. J. Toxicol. Environ. Health 047
Analysis of liver and kidney indices
Assay for the activities of aspartate aminotransferase
(AST), alanine aminotransferase (ALT) and alkaline
phosphatase (ALP) in serum were performed by the
method described by Reitman and Frankel (1957) using
Randox test kits. Serum urea concentrations was
measured enzymatically with urease and glutamine
dehydrogenase, creatinine levels were determined by the
kinetic calorimetric method with alkaline picrate and
bilirubin concentration was performed by the methods
described by Yakubu et al., (2007). Total protein, albumin
and globulin were assayed according to the method
described by George, (2009).
Histological examination
The excised organs were histologically examined by the
method described by Al-Hasawi and Al-Harbi (2014).
STATISTICAL ANALYSIS
Values obtained were expressed as Mean ± Standard
error of mean with analysis performed using SPSS
software version 20 for Windows (SPSS Inc. USA) at
p≤0.05 significant level.
RESULTS
Body and organ weight
The results of the variations in body and organ weights as
presented in Figures 1-3, showed a decrease in the body
weight of group 2 when compared to the normal control
(group 1) but significant increases (p≤0.05) in the body
weight in groups administered when compared to the
negative control group. Treatment with extracts of AML
resulted in an increase in the body weight within the group
as time progress with the values observed to be
significantly higher (p≤0.05) than the negative control
group but lower in the normal control. The body weights on
treatment with FZR were significantly higher (p≤0.05) also
followed a similar trend in comparison with the AML and
FZR treatment but the weights were significantly higher
(p≤0.05) with FZR than AML.
Figure 1: Body weights in zidovudine induced rats treated
with extract of Annona muricata leaves and Fagara
zanthoxyloide roots.
The results of the body weight in group 2 may culminate
the findings that the drug induces loss of appetite and may
elicit certain factors which results in a subtle derangement
of the neurochemical signaling with regards to appetite
stimulation in the brain (Satya et al., 1999). The resultant
effect would be a termination of neuromodulators related
to appetite thus reducing food intake and concomitantly
body weight loss. The results of group 4 and 5 may
suggest that extract co-administration possibly through the
presence of some bioactive compounds (Ekere et al.,
2019), may have cushioned or reversed the
neurochemical derangement thereby regulating food
intake and thus body weight (Figure1).
The weights of the liver and kidney were also observed to
decrease in group 2 when compared to the normal control
(group 1), while treatment with extracts of AML and FZR
resulted in an increase in the liver and kidney weights.
Figure 2: Liver weights in zidovudine induced rats treated
with extract of Annona muricata leaves and Fagara
zanthoxyloide roots"
Figure 3: Kidney weights in zidovudine induced rats
treated with extract of Annona muricata leaves and Fagara
Organ weight, judged as a sensitive indicator of toxicity
even in the absence of any morphological changes
(Mandal et al., 2012) was observed to reduce in the
negative control group when compared to the normal
control; possibly due to the reduction in body weights
observed during the study (Nirogi et al., 2013). The
reductions observed at weeks 4 and 6 may be linked to an
underlying pathological condition such as necrosis and
degenerative disorders (Miyauchi et al., 2013).The
increases in organ weight observed in treatment groups
may signify proper metabolism or histological disorder

Ekere et al. 048
(abnormal mass, contusions or tumours) which can be
ruled out on histological examination (Miyauchi et al.,
2013).
Liver and kidney indices
Results of the activities of liver enzymesare shown in
Figure 4-6. There was significant increase in the AST, ALT
and ALP activities after administration of 100mg ZDV/Kg
bw (Group 2) when compared to the normal control (Group
1). The positive control (Group 3) also showed an increase
in the serum activities of the liver function enzymes
investigated when compared to the normal control
(Group1) but asignificant reduction (p≤0.05) when
compared with the negative control (group 2). Extracts of
AML and FZR (Groups 4 and 5) resulted in significant
reductions (p≤0.05) in the activities of the liver function
enzymes at week 2 when compared with the negative
control (group 2). Prolonged simultaneous administration
(weeks 4 and 6) resulted in a reduction in the serum
activities of AST and ALT but an increase in the ALP
activity when compared with both negative and positive
control groups.
Figure 4-6: Liver enzyme activity (IU/L) in zidovudine
induced rats treated with extracts of Annona muricata
leaves and Fagara zanthoxyloide roots.
The significant increase (p≤0.05) in the activities of liver
enzymes in group 2 (Figure 4-6) may suggest
hepatotoxicity which progressed to weeks 6 (Belonwu et
al., 2013). Some researchers (Ogunka-Nnoka et al., 2019,
Obi et al., 2014 and Imafidon and Okunrobo 2012) have
reported that elevated levels of ALT, AST and ALP in
serum are associated with acute liver toxicity. Adebayo et
al., (2010) also reported that a deranged increase in ALP
activity as observed in this study may be an indication of
bone marrow disorder induced as a result of ZDV
administration. Hence the changes in AST, ALT and ALP
may suggest that ZDV induces hepatic damage and/or
disorders which relate to/or are associated with
osteotoxicity or myelotoxicity. The significant reductions in
the activities of liver enzymes on administration with
extracts as seen in groups 4-5 when compared with group
2 may also suggest the ability of these plants to confer
protection to the liver against ZDV induced toxicity;
confirming the beneficial effects of these plants in alcoholic
hepatitis conditions as proposed by folkloric medicine
dispensers (Adebayo et al., 2010). The decreases in the
ALP activity may also suggest its use in conditions which
results from bone marrow related toxicity.
The result of the administration of ZDV (group 2) on
selected liver biochemical indices shown in Figure 7-10
revealed significant reductions (p≤0.05) in the
concentrations of total protein, albumin and globulin when
compared with the group 1. The treatment with AML and
FZR resulted in a significant increase in the concentration
of these liver biochemical indices when compared to the
negative control (Group 2) while the values observed in the
positive control (group 3) were observed to be significantly
equivalent to the values in the AML and FZR treatment
groups.
Figure 7. Total protein concentration in zidovudine
induced rats treated with extracts of Annona muricata
leaves and Fagara zanthoxyloide roots
0
20
40
60
80
100
120
140
160
Group 1 Group 2 Group 3 Group 4 Group 5
AST(IU/L)
week 2 week 4 week 6
0
20
40
60
80
100
120
140
160
ALT(IU/L)
0
50
100
150
200
250
ALP(IU/L)

Figure 8. Albumin concentration in zidovudine induced
rats treated with extracts of Annona muricata leaves and
Fagara zanthoxyloide roots
The decrease in the concentration of total protein, albumin
and globulin in the negative control (Group 2) when
compared to the control suggest that ZDV may induce
hepatotoxicity (George, 2009) resulting in increase
amounts of p-proteins or decreased antibody production,
causing nephrosis and acute hemolytic anaemia (Ekam
and Udosen, 2012). The increase in the concentrations of
these liver biochemicals in AML and FZR treatment groups
may buttress publications that these extracts possess
hepatoprotective potentials mediated by antioxidants in
Wistar rats (Ekere et al., 2019).
Figure 9. Globulin concentration in zidovudine induced
Figure 10. Bilirubin concentration in zidovudine induced
The bilirubin concentration (Figure 10) was observed to
increase on the administration of ZDV (Group 2) when
compared to the normal control while simultaneous
administration with AML and FZR extracts (Groups 4 and
5) resulted in significant reduction (p≤0.05) in the bilirubin
concentration at week 2 when compared with the negative
control and further reduction as time progressed. The
increase in the level of bilirubin may be possibly caused by
an increase in haem metabolism (Amadiet al., 2018) as
bilirubin has been observed to accumulate from the
breakdown of haemoglobin, a key component of red blood
cells (Imafidon and Okunrubo, 2012). It may also be a sign
of hepatotoxicity displayed as impairment in the excretory
function of the liver or a compromise in its overall
functioning as the liver is responsible for the removal of
bilirubin from the blood and excreting it through the bile
(Senou, et al., 2017).
The serum concentrations of urea and creatinine in the
negative control group (Table 1) were observed to
significantly reduce (p≤0.05) on administration of ZDV in
group 2 when compared with the normal control. However,
the simultaneous administration with extracts of AML and
FZR resulted in a significant increase (p≤0.05) in the
serum concentrations of urea and creatinine at week 2, 4
and 6.
Table 1: Kidney indices in zidovudine-induced rats treated with extracts of Annona muricata leaves and Fagara
GRP Urea (mmol/L) Creatinine (µmol/L)
Week 2 Week 4 Week 6 Week 2 Week 4 Week 6
Group 1 5.69±0.20a
5.69±0.20a,b
5.69±0.20c
39.70±0.16a
39.70±0.16a,c
39.70±0.16c
Group 2 4.57±0.18b,c
4.15±0.02a,b
4.08±0.20a,c
30.35±0.01a
28.15±0.03a,d
24.34±0.04a,c
Group 3 5.24±0.28e
5.15±0.04a,d
4.94±0.03c,d
48.61±0.17a,c
46.13±0.03e
44.91±0.23a,e
Group 4 5.34±0.02a,d
5.47±0.05c
5.56±0.30a,e
46.42±0.02a
50.14±0.03b,c
53.39±0.01a,b
Group 5 5.31±0.03c,e
5.37±0.02b,c
5.44±0.03c
49.01±0.04b.e
50.07±0.08b
52.14±0.04a,e
Values expressed as Mean ± SEM of triplicate determination. Values with same superscript are statistically significant
(p≤0.05).
0
1
2
3
4
5
6
7
8
9
10
Globulin(g/L)

Ekere et al. 050
The urea and creatinine concentrations have been
reported to serve as reliable markers of the functionality of
the kidney (Belonwu et al., 2013), as such the decrease in
the concentrations would signify that ZDV results in a
decrease in the optimal functionality of the kidney possibly
resulting in nephrotoxicity as reported by Amadi et al.,
(2018). The increase in the serum urea and creatinine
concentrations on administration with extracts may
suggest that the extracts of AML and FZR prevent
nephrotoxicity induced by ZDV by a mechanism not
explored in this study (Ogunnka-Nnoka et al., 2012).
Histological examination
An examination of the liver of group 1 showed the
hepatocytes in normal architecture radiating from the
portal triad (Plate 1). Administration of 100mg ZDV/Kg B.W
resulted in severe dilation, congestion of blood vessel
transversing the liver and alterations in the architecture of
the hepatocytes which progressed towards necrosis and
sinusoidal infiltrations at week 6 (Plates 2-4).
Plate 1. Liver of normal control group showing
hepatocytes arranged in rolls radiating from the portal triad
along with a few dilated hepatic veins
Treatment with AML showed hepatocytes with preserved
architecture when compared with the negative control.
Slight dilation in the hepatic cords and single cell necrosis
was also observed on prolonged administration with AML
(Plates 8-10). Prolonged FZR administration resulted in
hepatic regeneration at week 4 with a decrease in hepatic
infiltration and congestions observed at week 6 (Plates 12
and 16).
Sinusoidal congestion and dilations have been reported by
Adisa et al., (2014) as an important marker of early onset
hepatotoxicity. The necrosis observed in the negative
control group serves as a sign of hepatic degeneration,
which in combination with the aforementioned signs may
suggest that ZDV may induce hepatic damage at the
dosage administered .According to Akinnawo et al.,
(2005), the architecture for the group administered with
AML may signify that the extract confers hepatoprotective
abilities through the presence of several antioxidants
(alkaloids, phenols, tannins), anti-inflammatory agents
(norchelerythine, α-humlene, β-pinene, zinc, fiber),
myleoregenerative and tissue regenerative agents (amino
acids, zinc, calcium, folate, vitamin B12) as seen in Plate 8-
9 (Ekere et al., 2019, Adisa et al., 2014.The observations
in the group administered with FZR may also signify a
regression in the observed deleterious effects of ZDV on
administration indicating a protective effect conferred on
the hepatocytes by the extracts.
Plate 2. Liver of Negative control group at
week 2 showing severe dilation and
congestion of blood vessels with altered
architecture
week 4 showing dilation and portal vein
congestion
week 6 showing marked sinusoidal congestion
and necrosis
Plate 5. Liver of group 3 at week 2
showing congestion and dilatation in
blood vessels.
showing hepatocytic dropout and
formation of rosette.
showing hyalinization and
progressive lymphocytic infiltration.

The kidney of the normal control group showed normal
architecture especially with the renal corpusles, tubules
and connecting ducts (Plate 14). The administration with
ZDV resulted in hypoplasia of the cells with swellings
observed at the epithelium of the renal tubules. The co-
administration with extracts of AML and FZR resulted in
the kidneys displaying normal architecture but with slight
dilations observed in the glomeruli.
showing preserved architecture and
slight blood sinusoid dialation.
showing distorted hepatic cord.
showing single cell necrosis and
esinophilic infiltration.
showing normal architecture with
focal vocalization
showing hepatic regeneration
showing decrease in hepatic
infiltration and congestion
Plates 15, 16, 17. Kidney of group 2 at week 2, 4 and 6 showing glomerulus was observed to be hyperplastic with renal
tubules epithelium showing signs of swellings
Plates 18, 19, 20. Kidney of group 3 at week 2, 4 and 6 showing collecting tubules lined with the relatively low simple
cubic epithelium.
Plates 14. Kidney of group 1 showing kidney cortex with normal structure of renal corpuscles, renal tubules and collecting ducts

Ekere et al. 052
Hyperplasia observed in the negative control group has
been linked to a regression in the development of the
kidney cells and reported by Adewole et al., (2006) as an
early sign of renal adaptations to toxins and possibly
nephrotoxicity. The normal architecture observed on co-
administration with AML may further buttress the findings
of Ekere et al., 2019 which suggested that the extracts
contained anti-oxidative agents (alkaloids, tannins,
phenols) and anti-inflammatory agents (norchelerythine,
α-humlene, β-pinene, zinc, fiber) which confer some
degree of protection to developing kidney cells hence
imitating nephroprotectivity.
CONCLUSION
The administration of zidovudine resulted in hepatotoxicity
and nephrotoxicity which were observed to be reduced to
some degree when extracts of AML and FZR were
administered as seen with the results of histological
investigations and liver and kidney indices investigated.
The impact of the extracts on these liver and kidney indices
and body and organ weight may suggest that these plants
may be hepatoprotective and nephroprotective to some
degree and may also be used in anorexigenic conditions
to boost body weight.
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Accepted 24 July 2019
Citation: Ekere, O.U., Ogunka-Nnoka, C.U., Monago-
Ighorodje, C.C. (2019). Hepatotoxicity and Nephrotoxicity
Studies of Ethanol Extracts of Annona Muricata Leaves
and Fagara Zanthoxyloide Roots on Zidovudine-Induced
Wistar Rats. International Journal of Toxicology and
Environmental Health, 4(1): 045-053.
Copyright: © 2019 Ekere et al. This is an open-access
article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium,
provided the original author and source are cited.

Hepatotoxicity and Nephrotoxicity Studies of Ethanol Extracts of Annona Muricata Leaves and Fagara Zanthoxyloide Roots on Zidovudine-Induced Wistar Rats

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Hepatotoxicity and Nephrotoxicity Studies of Ethanol Extracts of Annona Muricata Leaves and Fagara Zanthoxyloide Roots on Zidovudine-Induced Wistar Rats