Peroxisome Proliferator Activator Receptor (PPAR)- γ Ligand, but Not PPAR- α , Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver.

Azza A. K. El-Sheikh,Rehab A. Rifaai

doi:10.1155/2014/626319

Abstract

Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.

Highlights

Cyclophosphamide (CP) is a synthetic alkylating agent that has for long been successfully used in treatment of cancer and autoimmune diseases, as well as in the prevention of organ transplantation rejection [1]
The objective of this study is to establish the potential use of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, FEN, and PIO, respectively, as supplementary adjuvant to protect against CP-induced hepatotoxicity and to investigate the pharmacological mechanisms involved
Kits for examining total bilirubin, albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in serum, as well as reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione S-transferase (GST) in liver homogenate were purchased from Biodiagnostic (Egypt)

Summary

Introduction

Cyclophosphamide (CP) is a synthetic alkylating agent that has for long been successfully used in treatment of cancer and autoimmune diseases, as well as in the prevention of organ transplantation rejection [1]. Despite of its tumor selectivity and wide range of clinical applications, CP is known to cause multiorgan damage that result in severe morbidity and might end fatally [2]. CP-induced hepatotoxicity may occur at high chemotherapeutic dosage [7] or even at lower concentrations attained during treating patients with autoimmune diseases [8, 9]. The mechanisms involved in CP-induced hepatotoxicity are not completely clarified. It has been proposed that administration of CP might cause impairment of cellular respiration due to damage of mitochondrial energy converting mechanisms [10], which may interfere with hepatic intracellular oxidant/antioxidant balance and lead to accumulation of reactive oxygen species [11]. The resultant oxidative stress may trigger nuclear factor-κB (NF-κB) inflammatory pathway, which increases hepatic intracellular proinflammatory cytokines as tumor necrosis factor (TNF)-α [12]

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