Effect of Short-Term Tacrolimus Exposure on Rat Liver: An Insight into Serum Antioxidant Status, Liver Lipid Peroxidation, and Inflammation

N Fatima,A Tayyeb,I Ashfaq,S Ambreen,A R Satoskar,N Sheikh,S Oghumu,B K Jha,N Ryan,T Akhtar,Agnieszka Dobrzyn

doi:10.1155/2021/6613786

Abstract

Tacrolimus (TAC) is an immunosuppressive drug, optimally used for liver, kidney, and heart transplant to avoid immune rejection. In retrospect, a multitude of studies have reported effects of TAC, such as nephrotoxicity, diabetes, and other complications. However, limited information is available regarding short-term exposure of TAC on the liver. Therefore, the present study was designed to unravel the effects of short-term exposure of TAC on a rat model. The animal model was established by TAC administration for 6, 12, 24, and 48 h time points. Liver histopathological changes were observed with PAS-D, reticulin stain, and immunostaining of PCNA and CK-7 coupled with glycogen quantification in a liver homogenate. TUNEL assay was performed to evaluate the DNA damage in the liver. Concentration of GSH and activities of SOD and CAT in the serum were measured to assess the antioxidant status, whereas liver tissue MDA level was measured as a biomarker of oxidative stress. Hepatic gene expression analysis of IL-10, IL-13, SOCS-2, and SOCS-3 was performed by RT-PCR. Results revealed marked changes in liver architecture of all TAC-treated groups, as evidenced by sinusoid dilation, hepatocyte derangement, glycogen deposition, and collapsed reticulin fibers. Significant increase in PCNA and CK-7 immunostaining along with the presence of TUNEL-positive cells was revealed in treatment groups as compared to the control group. Serum antioxidant enzyme status was markedly decreased, whereas the liver MDA level was increased in TAC treatment groups indicating oxidative stress induction. The gene expression profile of cytokines was significantly upregulated in treatment groups highlighting an inflammatory response. In conclusion, results of the current study propose that even a short-term TAC exposure can induce change in antioxidant status and lipid peroxidation. Therefore, these factors should be considered to avoid and minimize immunosuppression-related issues in a prolonged course of treatment.

Highlights

Tacrolimus (TAC) is one of the widely used immunosuppressive drugs (ISD) for the prophylaxis of transplant patients [1]
The findings of this study revealed evident liver damage and glycogen deposition by significantly altering the liver architecture and change in antioxidant status of serum GSH and superoxide dismutase (SOD), CAT, and liver lipid peroxidation, along with DNA damage, proliferating cell nuclear antigen (PCNA) and cytokeratin 7 (CK-7) expression, and altered gene expression of cytokines
Oxidative hepatic damage and change in liver architecture with significant decrease in GSH concentration, inhibition of SOD and CAT activity, and increased MDA level have been previously reported in a liver toxicity model of rats [31, 32], and a link between change in antioxidant status and liver histopathology owing to liver injury has been described [33]

Summary

Introduction

Tacrolimus (TAC) is one of the widely used immunosuppressive drugs (ISD) for the prophylaxis of transplant patients [1]. TAC belongs to the category of calcineurin inhibitor (CNI); these drugs work by inhibiting calciumdependent events and are being used for liver transplantation since 1998 [2, 3]. Myriads of adverse effects and contraindications of TAC have been recently reported in transplant patients which include hepatotoxicity, encephalopathy, diabetes mellitus, nephropathy, increased susceptibility to COVID-19, and other infectious diseases, owing to immunosuppression [6,7,8,9,10]. Previous studies have reported nephrotoxicity in patients receiving TAC as immunosuppressive therapy after liver transplant. Previous studies have reported development of hepatic infarction in post liver transplant patients, as an effect of TAC [13]. Immunosuppressive drugs have some off target effects which may lead to production of reactive oxygen species (ROS) and induction of apoptotic cell death due to impaired mitochondrial and T cell functions [14]. Liver-targeted management should be taken into account to avoid liver complications [15, 16]

Methods

Results

Conclusion