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Available online at ajdhs.com 

Asian Journal of Dental and Health Sciences 
Open Access to Dental and Medical Research 

Copyright  © 2023 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 
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original author and source are credited  

 

 

Histopathological and Biochemical Effect of Vitamin C and D on 
Phosphine-Induced Hepatotoxicity in Wistar Rats 

Moronkeji Akinpelu1, Solomon Matthias Gamade2 , Frederick Akinbo3, Temidayo Daniel Adeniyi1, 
Adebowale Funmilola Elizebeth4 and Emmanuel Ifeanyi Obeagu5 * 

1 Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Medical Sciences, Ondo State, Nigeria 
2 Department of Medical Laboratory Science, Faculty of Allied Health Sciences, Bingham University Karu, Nasarawa State, Nigeria 
3 Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, University of Benin, Edo State, Nigeria 
4 Department of Medical Laboratory Science, Achievers University Owo, Ondo State, Nigeria 
5 Department of Medical Laboratory Science, Kampala International University, Uganda 

Article Info: 
_______________________________________ 
Article History: 
Received 02 April 2022      
Reviewed  08 May 2023 
Accepted 27 May 2023 
Published 15 June 2023 

_______________________________________ 
Cite this article as:  

Akinpelu M Gamade SM, Akinbo F, Adeniyi TD, 
Elizebeth AF, Obeagu EI, Histopathological and 
Biochemical Effect of Vitamin C and D on 
Phosphine-Induced Hepatotoxicity in Wistar 
Rats, Asian Journal of Dental and Health 
Sciences. 2023; 3(2):18-22 

DOI: http://dx.doi.org/10.22270/ajdhs.v3i2.40        

_______________________________________
*Address for Correspondence:   

Emmanuel Ifeanyi Obeagu, Department of 
Medical Laboratory Science, Kampala 
International University, Uganda 
Email: emmanuelobeagu@yahoo.com   

Abstract 
___________________________________________________________________________________________________________________ 

Background: Aluminum phosphide is becoming a very common agent for self-poisoning. The lack of specific antidote 
for phosphide poisoning has aroused the current interest of research.  

Objectives: This study aimed to investigate the possible protective effect of Vitamin C and D in phosphine-induced 
hepatotoxicity in Wistar rats.  

Methods: In this experimental study, 20 Wistar rats were randomly divided into five groups ( n = 12). Group I was 
apparently normal Control Group. Groups II-V were induced with 2.5 mg/kg ALP. Groups II was without further 
treatment while Groups III-IV received vitamin C at 100mg/kg/bw and vitamin D at 10mg/kg/bw. Group V was co-
administered with vitamin C at 100mg/kg/bw and vitamin at 10mg/kg/bw. The treatments lasted for 28 days. 

 Results: The results showed that Vitamin C and D (P<0.05) increased antioxidant capacity. Combined active 
constituents of the Vitamin C and Vitamin D raised the GPX antioxidant activities when compared to the phosphine 
poisoned group treated individually with Vitamin C and D. The combined activities of Vitamin C and Vitamin D showed 
the highest antioxidant effect as compared with the control   

Conclusion: The combined activities of Vitamin C and D supplementation improved the antioxidant defense system 
and histology of the liver in phosphine poisoning. 

Keywords: Metal phosphide, Carotene, Liver cell damage, Poison 

 

 

INTRODUCTION 

The agricultural revolution and the growing use of pesticides 
in improving agricultural produce have brought their share of 
downsides in the form of pesticide poisoning1. About 300,000 
deaths worldwide occur annually as a result of pesticide 
poisoning2,3. Additionally, self-intoxication accounts for more 
than 33% of suicides worldwide4. Aluminum phosphide (ALP) 
is the most common pesticides used for the safe storage and 
transportation of grains especially in Asian, Middle Eastern, 
and African countries5,6. Unfortunately, considering several 
health outcomes, it is becoming a very common agent for self-
poisoning7,8,9. In Nigeria, ALP is sold in the form of a tablet, 
granules, or powder as phostoxin, justoxin, cejphos, multiphos, 
force toxin. When it is, metal phosphides generate toxic 
phosphine gas when ingested or inhaled by humans as a result 
of the stomach's diluted acid content, causing multisystem 
toxicity10,11. The easy availability of ALP and it growing use for 
both agricultural and non-agricultural purposes is a public 
concern due to increasing number of suicide cases12. 

Vitamin D is essential for a wide range of non-classical 
functions and its deficiency has been linked to several chronic 
disorders including diabetes and cardiovascular disease13. It 
has been reported to inhibit iron-dependent lipid peroxidation 
and its antioxidant properties are compared to that of the 
anticancer medication Tamoxifen14. Vitamin D uptake has 
shown to prevent destruction of hepatocytes secondary to 
phosphine-induced lipid peroxidation15. Although there no 
available report, some experimental studies suggested that 
vitamin C and carotene could ameliorate the effects of 
oxidative phosphine16, 17. 

The lack of specific antidote for aluminum phosphide 
poisoning has aroused our interest. This study aimed to 
investigate the possible protective effect of Vitamin C and D in 
phosphine-induced hepatotoxicity in male Wistar rats.  

METHODOLOGY 

The study was approved by the Biomedical Research and 
Ethics Committee of the Ministry of Agriculture and Forestry, 
Akure, Ondo State, Nigeria (MNR/V384/9). The experimental 
animals were handled following the International Humane 

                       Open Access                                                                                                                                                                                                         Research Article                                          

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Animal Care Standards18. Twenty (20) inbred Wistar rats 
weighing 180±20g were used and maintained under the 
standard husbandry condition (between 22-25°C, 12 hours 
light and 12 hours dark) in the Animal House. Animals were 
fed ad libitum. 

Chemicals and reagents 

Superoxide peroxide and glutathione peroxide reagents were 
purchased from the R and D System in Minneapolis, 
Minnesota, in the United States. Commercial enzyme-linked 
immunosorbent test (ELISA) kits for tumour necrosis factor-
alpha (TNF-α) and interleukin 6 (IL-6) were purchased from 
Creative Diagnostics in Shirley, New York, 11967, USA. From 
stock chemicals of analytical grade, Haematoxylin and Eosin 
(H&E), PBS solution, and 10 percent neutral buffer formalin 
were prepared. 

Drugs  

Aluminum phosphide (ARYSTA Life Science South Africa Pty 
Ltd) was purchased in Lagos Nigeria. PARTAN-C Vitamin C 
tablet manufactured by Kunimed Pharmachem Limited, Lagos 
Nigeria, and Health Aid Vitamin D 1000IU produced by Health 
Aid Plus Limited, Nigeria. 

Experimental Design 

Twenty (20) adult male wistar rats obtained from the Animal 
Holding of the Department of Anatomical Sciences, University 
of Medical Sciences, Ondo state were randomly allotted into 
five groups consisting of four rats each. Each of the test groups 
was exposed to aluminum phosphide at a standard dosage of 
2.5 mg/kg/body weight.  

Group I was the apparently normal control group 

Group II was induced with 2.5 mg/kg ALP without further 
treatment 

Group III was the ALP-exposed group administered with 
vitamin C at 100mg/kg/bw 

 Group IV was the ALP-exposed group administered with 
vitamin D at 10mg/kg/bw 

 Group V was the ALP-exposed group co-administered with 
vitamin C at 100mg/kg/bw and vitamin at 10mg/kg/bw 
respectively. 

The treatments lasted for 28 days. 

Induction of hepatotoxicity 

Two and a half percent solution of the ALP was prepared and 
used to induce phosphine toxicity via an orogastric tube. 

Necropsy 

Upon completion of the experiment,  the Wistar rats were 
euthanized and the liver of the rats was carefully excised and 
immediately transferred in 10% neutral buffered formalin for 
adequate fixation followed by histological processing for 
microscopic studies while the liver samples for biochemical 
analysis were rinsed in freshly prepared 0.1 mol/L phosphate-
buffered saline (PBS, pH 8.0), followed by homogenisation and 
centrifuged at 3000 revolutions per minute for 20 min at 4°C. 
The supernatant obtained was preserved at -80°C for the 
estimation of biochemical analytes. 

Histopathological study 

Upon completion of fixation in 10% Neutral buffered formalin. 
The liver was processed for light microscopic study using an 
automatic tissue processor machine (Thermo Scientific Spin 
Tissue Processor, STP120, Frankfurt, Germany). The tissues 
were dehydrated in graded alcohol concentrations, cleared in 
two changes of xylene, infiltrated in two changes of wax bath, 
and lastly embedded in paraffin wax. Olympus binocular light 
research microscope was used to histologically assess the thin 
sections of 4 microns stained with Haematoxylin and Eosin 
(H&E). Micrographs were taken with a Kodak Digital Camera 
(Kodak Easyshare C183). 

Biochemical analysis 

The activity of superoxide dismutase (SOD) was determined 
by the method of Misra et al19. While glutathione (GPx) activity 
was assayed according to Rahman et al20. Levels of 
interleukin-6 (IL-6) and tumour necrosis factor-ALPha (TNF-
α) were evaluated using Sandwich ELISA kit protocols 
described by the manufacturer. 

Statistical Analysis 

The data were analysed using statistical software for social 
sciences (SPSS) 23.0 version. Data were presented using mean 
standard deviation (mean SD) for all quantitative values, and 
one-way analysis of variance (ANOVA) was used for 
comparisons between the groups. Quantitative values of 
p<0.05 were considered statistically significant. 

RESULTS 

Biochemical Findings 

Table 1 Showed the Immunomodulatory effect of Vitamin C 
and D on IL-6 and TNF-α. Regarding the GPX and SOD 
activities, IL-6 and TNF-α levels were significantly 
(p<0.00001) reduced compared to the control group. However, 
combined active constituents of ALP+Vit.C &Vit D raised the 
GPX antioxidant activities when compared to the phosphine 
poisoned group treated individually with Vitamin C and D.  
Combined activities of Vit.C &Vit D showed the highest 
antioxidant effect as compared with the control (Table 1).

  

Table 1: Immunomodulatory effect of IL-6 and TNF-α  

Parameter Normal control 

 
Positive control (ALP-
induced animals) 

ALP+Vit. C      
(100 mg/kg/bw) 

ALP+Vit. D          
(10 mg/kg/bw) 

ALP+Vit.C &Vit D.  

SOD ( U/mg) 36.89±0.27 2.90±0.09 2.08±0.02 2.10±0.03 2.58±0.18 

GPx ( µmoles ) 116.92±0.63 39.90±0.36* 39.56±0.42* 34.95±0.22* 43.29±0.88* 

IL-6 27.62±0.24 123.24±7.06* 231.29± 3.53* 224.73±9.38* 234.7±2.29* 

TNF alpha 217.32±1.07 525.52±3.74* 473.76±8.98* 570.86±19.73* 491.23±2.97* 

Values were expressed as mean value ± standard deviation (SD).*mean values were significantly different compared to the Normal control at P≤ 
0.05.#mean values were significantly different compared with the control 

 



Akinpelu et al                                                                                                                             Asian Journal of Dental and Health Sciences. 2023; 3(2):18-22 

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0

100

200

300

400

500

600

TNF alpha

Normal control

ALP

ALP+Vit.100mg/kg

ALP+10mg/kg

ALP+100mg Vit C+Vit D
10 mg/kg

0

50

100

150

200

250

Glutathione Peroxidase IL6

Normal control

ALP

ALP+Vit C 100mg/kg

ALP+Vit D 10mg/kg

ALP+Vit C
100mg+Vit D
10mg/kg

 

Figure 1: Immunomodulatory effect of Vitamin C and D on ALP poisoning 

Histopathological result 

      
ALP-induced liver

Normal control liver

ALP +Vit. C 100 mg/kg

Figure 1: Histological representation of normal liver cells showed a central vein (red arrow) and radiating chords of hepatocytes 
(black arrow) with sinusoids devoid of congestion. ALP-induced liver exhibited hepatocyte vacuolation (black arrow), sinusoidal 
congestion (blue arrow), and nuclear fragmentation (green arrow). ALP-induced liver administered with Vit. C 100 mg/kg illustrated 
regenerative changes (pyknotic nuclei) characterized by reduced congestion in the sinusoidal space and the absence of nuclear 
fragmentation of hepatocytes. (H&E. X 400).    

ALP +Vit. D 10 mg/kg ALP +Vit. C 100 +Vit. D 10 mg/kg
 

Figure 3: Histological representation of ALP-induced liver administered with Vit. D 10 mg/kg showed interstitial hemorrhage 
(green), and pyknotic nuclei (blue) which is suggestive of reparation changes. ALP-induced liver treated with Vit. C +Vit. D showed 
apparently normal liver cells with a significant reduction in sinusoidal congestion. (H&E. X 400). 



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DISCUSSION 

Hepatic damage is a major cause of death due to phosphine 
poisoning21. To date, there is no substantial treatment for the 
several cases reported22. This study aimed to investigate the 
immunohistopathological effect of Vitamin C and D in 
Aluminium phosphide poisoning. The present study showed 
that ALP-induced liver exhibited hepatocyte vacuolation, 
sinusoidal congestion, and nuclear fragmentation. Consistent 
with our result, previous studies has reported hepatocyte 
vacuolation, sinusoidal congestion, fatty liver changes, 
centrilubolar necrosis, and destruction of nucleolus of 
hepatocytes in phosphine- poisoning22,23. Haghi et al 24 
concisely discussed the mechanisms of hepatocyte phosphine-
induced cytotoxicity, highlighting the production of reactive 
hydroxyl radicals, induction of cellular hypoxia, and free 
radical-mediated injury in addition to the inhibition of 
cytochrome C-oxidase and other essential cellular 
enzymes25,26,27. Vitamin C administration at a dose of 100 
mg/kg exhibits a recovery in the ALP-induced hepatotoxicity 
with reparation features suggestive of regenerative changes. 
In addition, the sinusoidal congestion subsided with no 
evidence of nuclear fragmentation in the group. Interstitial 
haemorrhage and the presence of pyknotic nuclei were seen in 
the liver of the ALP-induced toxicity in rats administered 
Vitamin D at a dose of 10mg/kg. The liver of the ALP-exposed 
rats co-administered with vitamin C and D appeared 
apparently normal with a significant reduction in the 
sinusoidal congestion.  

According to the present study, phosphine decreases SOD and 
GPX activities in the liver tissue and this effect is slightly 
inhibited by the concurrent administration of Vitamins C and 
D. Documented evidence abound, antioxidant supplements 
especially vitamin C and vitamin D relieve the body of stress 
associated with phosphine poisoning28. Studies have also 
revealed that vitamin C enhance the strength of the 
antioxidant defense system by increasing the antioxidant 
capacity and controlling reactive oxygen species29. Vitamin D 
reduces ROS and pro-inflammatory cytokines possibly by 
improving cellular Glutathione levels30,31. 

CONCLUSION 

 In conclusion, our finding showed that the combination of Vit 
C and Vit D supplementation improved the antioxidant 
defense system and improved the histopathology of the liver 
in phosphine poisonng and reduces oxidative stress. 

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