Papel da isoforma óxido nítrico sintase na lesão hepática induzida por nimesulida

Abstract

The liver is the main organ involved in the metabolism of xenobiotics, playing essential roles in the biotransformation and excretion of potentially toxic compounds. Nimesulide, a nonsteroidal anti-inflammatory drug selective for the enzyme cyclooxygenase-2, has wide clinical application, but its prolonged or indiscriminate use is associated with the occurrence of drug-induced liver injury. This toxicity may involve mechanisms such as oxidative stress, mitochondrial dysfunction and exacerbated activation of inflammatory responses. Nitric oxide, produced by nitric oxide synthase enzymes, plays a dual role, and can be protective or deleterious, especially when produced in excess by the inducible isoform. Therefore, the present study aimed to

investigate the role of nitric oxide and the nitric oxide synthase isoform in nimesulide- induced hepatotoxicity. For this purpose, the experimental protocol for inducing

hepatotoxicity in mice through the nimesulide overdose model in male Swiss mice (20- 30 g) from the General Bioterium of the Federal University of Piauí was used. The project was approved by the Ethics Committee on Animal Experimentation of the Federal University of Delta do Parnaíba (Protocol: 10/2021). For this, mice were divided into five experimental groups treated as follows: Saline (0.9% saline solution v.o.); nimesulide (200 mg/kg v.o.) + DMSO 4% (150 μL i.p.); L-NAME (non-specific antagonist of induced nitric oxide synthase; 3 mg/kg i.p.) and 1400W (specific antagonist of induced nitric oxide synthase; 2.5 mg/kg i.p.). Liver injury was induced by oral administration of nimesulide 200 mg/kg. After euthanasia, blood was collected and the liver was removed for biochemical measurements, such as: myeloperoxidase; malondialdehyde; glutathione; aspartate aminotransferase; alanine aminotransferase; bilirubin and albumin; in addition, the liver weight/animal weight ratio was evaluated. The results obtained from the ratio between liver weight and total animal weight; oxidative stress by quantifying glutathione and malondialdehyde in the liver homogenate; determination of the concentration of the enzyme myeloperoxidase in the liver and hepatic markers of alanine aminotransferase; aspartate aminotransferase; bilirubin and albumin showed that liver injury induced by nimesulide in mice promoted inflammatory, oxidative and biochemical parameter changes. Therefore, the use of selective inhibitors of induced nitric oxide synthase as hepatoprotective agents in nimesulide-induced hepatotoxicity demonstrated considerable protection to the liver, with attenuation of the inflammatory parameters evaluated. These findings indicate that induced nitric oxide synthase may be a promising therapeutic target in the prevention of drug-induced liver injury associated with nimesulide and reinforce the importance of the rational use of nonsteroidal anti-inflammatory drugs in clinical practice.