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

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.

Locally controlled release of immunosuppressive promotes survival of transplanted adult spinal cord tissue

“…While liver and kidney of the aSCT + TAC@TGM group exhibited normal histological appearance. These results were consistent with earlier studies, which reported that obvious toxic effects of high-dose (aSCT + TAC-TP group) or long-term systemic use (aSCT + TAC-IP group) of TAC on liver and kidney [ 18 , 50 ].…”

“…(Sakura Finetek Inc.) and then frozen sectioned (10 μm) using a Leica CM1950 cryostat (Leica Camera Inc.). Hematoxylin–eosin (HE) staining was applied for general morphology observation according to the previous method [ 18 ]. Image-J software (Wayne Rasband, National Institutes of Health) was used to calculate the percentage of area occupied by inflammatory cells in the visual field.…”

Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients

“…Its greater immunosuppressive effects and lower incidence of adverse reactions (compared with ciclosporin) have established itself as one of the common immunosuppressive protocols in organ transplantation (Kelly et al., 2004; Rawal & Yazigi, 2017). Currently, the most commonly used immunosuppressive agent is Tac in liver transplant patients, but the similar dosages of effectiveness and toxicity cause adverse effects, which limits its clinical application in liver transplantation (Fatima et al., 2021).…”

“…Currently, the most commonly used immunosuppressive agent is Tac in liver transplant patients, but the similar dosages of effectiveness and toxicity cause adverse effects, which limits its clinical application in liver transplantation (Fatima et al, 2021).…”

Quercetin ameliorates thioacetamide‐induced hepatic fibrosis and oxidative stress by antagonizing the Hedgehog signaling pathway

“…The primer pairs used were Shh (forward: CAATTACAACCCCGACATCA, reverse: AGTCACTCGAAGCTTCACTCC), Ihh (forward: TCAGCGATGTGCTCATTTTC, reverse: CCTCGTGAGAGGAGCATAGG), Ptch (forward: ATTTCTTGCCCTTGGTGTTG, reverse: GAAGGCAGTGACATTGCTGA), Smo (forward: AGAAGGCCTTGGCAATCA, reverse: GAAGCCCATTCCTGATTGTG), Hhip (forward: TGTGCCGTGGATCGAC, reverse: GATCTCCGAACACGTAGCTT), Gli‐3 (forward: CCCTCTCTCCCTTATCGTG, reverse: AAGGCAAGTCTGGATACGTT), TNF‐α (forward: ACA AGG CTG CCC CGA CTA T, reverse: CTC CTG GTA TGA AGT GGC AAA TC), NFκβ (forward: CAT GGC AGA CGA CGA TCC TT, reverse: AAG GTA TGG GCC ATC TGT TGA), Socs3 (forward: AGCTCCAAAAGCGAGTACCA, reverse: TGACGCTCAACGTGAAGAAG), and GAPDH (forward: AGAGACAGCCGCATCTTCTT, reverse: TGCATTGCTGACAATCTTGA). Expressions were analyzed using RT‐PCR 25,26 …”