Biochemical and histological investigation of azathioprine and melatonin in rats


Published: Apr 19, 2024
Keywords:
Azathioprine Histological Liver Melatonin
AΑ Hussein
https://orcid.org/0000-0001-7680-4791
MΗ Ahmed
NG Mustafa
Abstract

ABSTRACT


Azathioprine (AZA) is a purine antagonist, also known as Imuran or Azapress, is a commonly prescribed immunosuppressive drug that is used in the management of many conditions (cancer, inflammatory bowel diseases, post-transplant immunosuppression, and various autoimmune diseases). However, their therapeutic role has been under debate because of their hepatotoxicity. Monitoring liver function in patients with hepatic impairment who are taking AZA is recommended. Melatonin (MEL) is a hormone usually produced at night by the pineal gland that acts to regulate the day and night cycle. Melatonin in supplements is usually made in a lab and is frequently used for the treatment of insomnia caused by shift work and jet lag. It is a well-known natural antioxidant, improving the hepatic detoxification system. There are numerous studies investigating the effects of MEL on liver injuries. Melatonin could control proliferation, reducing apoptosis, inflammation, and suppressing autophagic cell death in different pathophysiological conditions. The current study was undertaken to determine whether MEL could improve and ameliorate structural and biochemical changes in the liver that were induced by AZA. The 24 male adult rats were grouped as follows: The first group (G1) was given normal saline orally for 4 weeks and was listed as a control, while the second group (G2) was given AZA orally (20 mg/kg B.Wt.) for 4 weeks. MEL (10 mg/kg, B.Wt.) was given to the third group (G3) for four weeks. The fourth group (G4): given AZA (20 mg/kg B.Wt.) and MEL (10 mg/kg B.Wt.) for 4 weeks. Liver sections of the AZA-treated group showed degeneration and necrosis of hepatocytes with increased numbers of kupffer cells. Group 4 showed the normal architecture of liver tissue with increased numbers of kupffer cells. The serum biochemical profiles showed an increase in serum aspartate (AST) and alanine aminotransferase (ALT) enzymes, and a reduction in albumin and total protein in the group treated with AZA, while the liver function tests in the third and fourth groups showed a nonsignificant difference from the control group. We concluded from the results of this study that AZA induces structural and biochemical changes in the liver, and these effects could be improved by the administration of MEL in the last group.


Keywords: Azathioprine; Biochemical; Histological; Liver; Melatonin.

Article Details
  • Section
  • Research Articles
Downloads
Download data is not yet available.
Author Biographies
AΑ Hussein, College of Veterinary Medicine / University of Mosul

Lecturer in Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Mosul, Mosul, Iraq.

Specialty (General/ Major): BVMS (College of Veterinary Medicine) / Phd (Medical Biochemistry)

MΗ Ahmed, Alnoor University College/ Mosul / Iraq

Lecturer in Alnoor University Colleg/ PhD in histology

NG Mustafa, College of Veterinary Medicine / University of Mosul

BVMS (College of Veterinary Medicine)

MSc Biochemistry (College of Veterinary Medicine)

Professor Dr. (Biochemistry and Molecular Biology)

References
Abdi S, Abbasinazari M, Ataei S, Khanzadeh-Moghaddam N, Keshvari
N. (2021). Benefits and Risks of Melatonin in Hepatic and Pancreatic Disorders; A Review of Clinical Evidences. Iran J Pharm Res.
(3):102-109. doi: 10.22037/ijpr.2020.114477.14872.
Ahmad R, Gupta S, Haldar C. (2012). Age dependent expression of melatonin membrane receptor (MT1, MT2) and its role in regulation of
nitro sative stress in tropical rodent Funambuluspennanti. Free Radic
Res. 46(2):194-203.doi: 10.3109/10715762.2011.647690.
Ali DKH.(2018). Histopathological effect of azathioprine on liver, intestine and spleen of albino. Pakistan Journal of Biotechnology.
;15(3):621-5.
Aljumah AA, Al Jarallah B, Albenmousa A, Al Khathlan A, Al Zanbagi
A, Al Quaiz M, Al-Judaibi B, Nabrawi K, Al Hamoudi W, Alghamdi
M, Fallatah H. (2018). The Saudi association for the study of liver
diseases and transplantation clinical practice guidelines for management of autoimmune hepatitis. Saudi J Gastroenterol, 24(7):1-20.doi:
4103/sjg.SJG_159_18.
Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL.(2017). Evidence for the efficacy of melatonin in the treatment of primary adult
sleep disorders. Sleep Medicine Reviews. 1;34:10-22.doi: 10.1016/j.
smrv.2016.06.005.
Baydas G, Kutlu S, Naziroglu M, Canpolat S, Sandal S, Ozcan M, Kelestimur H. (2003). Inhibitory effects of melatonin on neural lipid
peroxidation induced by intracerebroventricularly administered
homocysteine. J Pineal Res. 34(1): 36-39. doi: 10.1034/j.1600-
x.2003.02939.x.
Björnsson ES, Gu J, Kleiner DE, Chalasani N, Hayashi PH and HoofnagleJH.(2017). “Azathioprine and 6-mercaptopurine-induced liver injury,” Journal of Clinical Gastroenterology, 51, (1):63-69,doi:
1097/MCG.0000000000000568.
Esteban-Zubero E, Alatorre-Jiménez MA, López-Pingarrón L,
Reyes-Gonzales MC, Almeida-Souza P, Cantín-Golet A, et al. (2016).
Melatonin’s role in preventing toxin-related and sepsis-mediated hepatic damage: A review. Pharmacol Res.105:108-20.doi: 10.1016/j.
phrs.2016.01.018.
Gisbert JP, González-Lama Y, Maté J. (2007). Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic
review. Am J Gastroenterol. 102(7):1518-27. doi: 10.1111/j.1572-
2007.01187.x.
Hindorf U, Lindqvist M, Hildebrand H, Fagerberg U, Almer S.(2006).
Adverse events leading to modification of therapy in a large cohort of
patients with inflammatory bowel disease. Aliment PharmacolTher.
;24(2):331-42.doi: 10.1111/j.1365-2036.2006.02977.x.
Kaymak E, Ünsal M, Akın A, Öztürk E, Ceylan T, Kuloğlu N, et
al.(2022).”Protective effect of melatonin on cisplatin-induced liver
injury in rats”. CukurovaMedical Journal.47:250-258https://dergipark.org.tr/en/pub/cumj/issue/68810/1029473.
Kostoglou-Athanassiou I. (2013). Therapeutic applications of
melatonin. TherAdvEndocrinolMetab. 4(1):13-24. doi:
1177/2042018813476084.
Ladrière M. (2013). [Current indications of azathioprine in nephrology]. NephrolTher. 9(1):8-12.doi: 10.1016/j.nephro.2012.08.002.
Mayo JC, Sainz RM, Antoli I, Herrera F, Martin V, Rodriguez C. (2002).
Melatonin regulation of antioxidant enzyme gene expression. Cell
Mol Life Sci. 59: 1706-1713.doi: 10.1007/pl00012498.
Montasser AOS, Saleh H, Ahmed-Farid OA, Saad A, Marie MS. (2017).
Protective effects of Balanitesaegyptiaca extract, Melatonin and Ursodeoxycholic acid against hepatotoxicity induced by Methotrexate
in male rats. Asian Pac J Trop Med. 10:557-65.doi: 10.1016/j.apjtm.2017.06.003.
Oleshchuk O, Ivankiv Y, Falfushynska H, Mudra A, Lisnychuk N. (2019).
Hepatoprotective Effect of Melatonin in Toxic Liver Injury in Rats.
Medicina (Kaunas). 24;55(6):304. doi: 10.3390/medicina55060304.
Reggio A, Spada F, Rosina M, Massacci G, Zuccotti A, Fuoco C,et
al.(2019). The immunosuppressant drug azathioprine restrains adipogenesis of muscle Fibro/Adipogenic Progenitors from dystrophic mice by affecting AKT signaling. Sci Rep. 13;9(1):4360. doi:
1038/s41598-019-39538-y.
Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin
L.(2016). Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 61:253- 78.doi: 10.1111/jpi.12360.
Relia S, Ekambaram V.( 2018). Pharmacological Approach to Sleep Disturbances in Autism Spectrum Disorders with Psychiatric Comorbidities: A Literature Review. Med Sci (Basel). 25;6(4):95. doi: 10.3390/
medsci6040095.
Roselli J, Innocenti T, Lynch EN, Parisio L, Macri G, Milla M,et
al.(2020). Increased Risk of Liver Cirrhosis during Azathioprine
Therapy for Crohn’s Disease. Case Rep GastrointestMed.doi:
1155/2020/6726384
Sayan M, Karabulut D, Ozdamar S. (2020). Assessment of the protective
and therapeutic effect of melatonin against thioacetamide-induced
acute liver damage. J BiochemMolToxicol. 34: e22450.doi: 10.1002/
jbt.22450.
Spinella R, Sawhney R, Jalan R. (2016). Albumin in chronic liver disease: structure, functions and therapeutic implications. Hepatol int. 10:124-
doi: 10.1007/s12072-015-9665-6.
Touhami S, Diwo E, Sève P, Trad S, Bielefeld P, SèneD,et al.(2019).
Expert opinion on the use of biological therapy in non-infectious uveitis. Expert OpinBiolTher, 19(5):477-90.doi:
1080/14712598.2019.1595578.
Wee JS, Marinaki A, Smith CH.(2011). Life threatening myelotoxicity
secondary to azathioprine in a patient with atopic eczema and normal thiopurinemethyltransferase activity. BMJ. 25;342:d1417. doi:
1136/bmj.d1417.
Zhang JJ, Meng X, Li Y, Zhou Y, Xu DP, Li S, Li HB. (2017). Effects of
Melatonin on Liver Injuries and Diseases. Int J Mol Sci. 18(4):673.
Published. doi:10.3390/ijms18040673