Role of Platelet-activating factor and HO-1 in mediating the protective effect of rupatadine against 5-fluorouracil-induced hepatotoxicity in rats

Hanaa Mohamed Khalaf,Fatma Alzhraa Fouad Abdelbaky,Ahlam Mohamed Abdalla,Sara Mohamed Naguib Abdel Hafez,Walaa Yehia Abdelzaher,Nermeen N. Welson

doi:10.1007/s11356-022-18899-4

Hanaa Mohamed Khalaf, Fatma Alzhraa Fouad Abdelbaky + Show 4 more

Open Access

https://doi.org/10.1007/s11356-022-18899-4

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Abstract

5-fluorouracil (5-FU) is a widely used chemotherapeutic drug, but its hepatotoxicity challenges its clinical use. Thus, searching for a hepatoprotective agent is highly required to prevent the accompanied hepatic hazards. The current study aimed to investigate the potential benefit and mechanisms of action of rupatadine (RU), a Platelet-activating factor (PAF) antagonist, in the prevention of 5-FU-related hepatotoxicity in rats. Hepatotoxicity was developed in male albino rats by a single 5-FU (150 mg/kg) intra-peritoneal injection on the 7th day of the experiment. RU (3 mg/kg/day) was orally administrated to the rodents for 10 days. Hepatic toxicity was assessed by measuring both liver and body weights, serum alanine aminotransferase and aspartate aminotransferase (ALT and AST), hepatic oxidative stress parameters (malondialdehyde (MDA), nitric oxide levels (NOx), reduced glutathione (GSH), superoxide dismutase (SOD)), and heme oxygenase-1 (HO-1). Inflammatory markers expressions (inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNFα), interleukins; IL-1B, IL-6), the apoptotic marker (caspase-3), and PAF were measured in the hepatic tissue. 5-FU-induced hepatotoxicity was proved by the biochemical along with histopathological assessments. RU ameliorated 5-FU-induced liver damage as proved by the improved serum ALT, AST, and hepatic oxidative stress parameters, the attenuated expression of hepatic pro-inflammatory cytokines and PAF, and the up-regulation of HO-1. Therefore, it can be concluded that RU pretreatment exerted a hepatoprotective effect against 5-FU-induced liver damage through both its powerful anti-inflammatory, antioxidant, and anti-apoptotic effect.

Highlights

Malignancy is the major cause of global death and no adequate therapeutic approaches are available
There was no significant difference in the serum activities of ALT and AST between the RU group and the control group
There was a significant improvement in the oxidative stress parameters with RU pretreatment (RU + 5-FU group) in comparison with the 5-FU group as indicated by the significant increase in Superoxide dismutase (SOD) and GSH along with the reduction of MDA and NOx levels (Table 2)

Summary

Introduction

Malignancy is the major cause of global death and no adequate therapeutic approaches are available. Chemotherapy is one of the most widely used agents to manage distinct types. Chemotherapeutic agents do not differentiate between normal and cancer cells leading to severe and undesirable toxicities. 5-FU, a pyrimidine analog anti-metabolite, is a common chemotherapeutic agent used for the treatment of different malignancies Al-Asmari et al (2016). 5-FU cytotoxic effect on malignant and normal proliferating cells is owing to its catabolic pathway and the production of three main reactive metabolites; 5-fluorouridine- 50-monophosphate, 5-fluoro-uridine-50-triphosphate, and 5-fluoro-20-deoxyuridine-50-triphosphate. These metabolites exert their cytotoxic action via the perturbation of thymidylate synthase and the synthesis of nucleic acids. These metabolites exert their cytotoxic action via the perturbation of thymidylate synthase and the synthesis of nucleic acids. 5-FU toxicity is mainly dose-dependent, and it varies among the patients causing occasional therapy discontinuation (Garg et al 2012; Rashid et al 2014)

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