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The Effects of Spironolactone in Preventing Bile Duct Ligation- Induced Hepatitis in a Rat Model

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The Effects of Spironolactone in Preventing Bile Duct Ligation- Induced Hepatitis in a Rat Model Iranian Journal of Pharmaceutical Research (2021), 20 (2): 35-44 DOI: 10.22037/ijpr.2020.112488.13786 Received: September 2019 Accepted: April 2020 Original Article The Effects of Spironolactone in Preventing Bile Duct Ligation- induced Hepatitis in A Rat Model Ahmet Özer Şehirlia*, Azime Kökeşb, Ayliz Velioğlu-Öğünçc, Şermin Tetikd, Naziye Özkane, Şule Çetinele, Serkan Sayınerf and Gül Dülgerb aDepartment of Pharmacology, Faculty of Dentistry, Near East University, 99138 Nicosia, North Cyprus, Mersin 10, Turkey. bDepartment of Pharmacology, Faculty of Pharmacy, Marmara University, 34722 Istanbul, Turkey. cVocational School of Health-Related Professions, Marmara University, 34722 Istanbul, Turkey. dDepartment of Biochemistry, Faculty of Pharmacy, Marmara University, 34722 Istanbul, Turkey. eDepartment of Histology and Embryology, School of Medicine, Marmara University, 34722 Istanbul, Turkey. fDepartment of Biochemistry, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Mersin 10, Turkey. Abstract Cholestasis is associated with the accumulation of bile acids and bilirubin in the hepatocytes and leads to liver injury. Pregnane X Receptor (PXR) coordinates protective hepatic responses to toxic stimuli, and this receptor was reported to stimulate bile secretion by increasing MRP2 expression. Since PXR activators were reported to be anti-inflammatory in the liver, PXR was proposed as a drug target for the treatment of chronic inflammatory liver diseases. We investigated the potential protective effect of spironolactone (SPL), an enzyme inducer, in hepatotoxicity induced by bile duct ligation in rats. Wistar Albino (250-300 g) rats were divided into the control group and the bile duct ligated (BDL) group. BDL group was divided into three subgroups; following BDL, for 3 days, the first group received propylene glycol (vehicle of SPL) (blinded), the second subgroup received spironolactone (SPL) (200 mg/kg oral), and the third subgroup received SPL for 3 days, starting 3 days after the bile duct ligation, in order to investigate if it has a healing effect after hepatitis had developed. The control group was sham-operated and received saline. At the end of the experiment, blood and tissue samples were collected. Serum TNF-α, NF- ĸB, bilirubin, IL-6 levels, ALT, AST, ALP activities and tissue MPO activity and oxidant damage increased after the bile duct ligation was significantly decreased following SPL administration. PXR and MRP2 activity showed an increase in the hepatocytes as a result of the treatment. In conclusion, it was observed that SPL administration significantly decreases liver inflammation and damage related to BDL. Keywords: Cholestasis; Inflammation; Multidrug resistance-associated protein 2; Pregnane X receptor; NF-ĸB; Spironolactone. Introduction acid accumulation in the liver is implicated as the principal cause of hepatotoxicity, leading Chronic cholestatic liver diseases are to reactive oxygen species formation and characterized by defective bile acid transport oxidative damage (1). from the liver to the intestine, caused by Disorders in the accumulation and secretion primary damage to the biliary epithelium. Bile of bile acids and bile salts in the liver are often * Corresponding author: reported to be caused by down-regulation in E-mail: [email protected] systems related to hepatic efflux transporters Özer Şehirli A et al. / IJPR (2021), 20 (2): 35-44 such as multidrug resistance-associated protein of the Marmara University (Approval no: 2 (MRP2) (1–4). MRPs are members of the 45.2010 mar). ABC superfamily of adenosine triphosphate- dependent transporters and are expressed in Surgery and Experimental Design various tissues, including the intestine, liver Four groups of 6 rats were formed in and kidneys. They facilitate the movement of our study. All animals were weighed at the various compounds, including bile acids, out beginning of the experiment. They were then divided into the control group, the BDL group, of the hepatocytes. Although the molecular the SPL1 group and the SPL2 group. All rats mechanisms related to this down-regulation were anesthetized (ketamine and 0.75 mg/kg phenomenon have not been fully elucidated, it chlorpromazine, i.p.), and the abdomen was is known that the activation of nuclear proteins opened via a midline laparotomy. In the control such as pregnane X receptor (PXR), which group (sham-operated), the rats were incised, is responsible for the increase in expression the incision was resealed, and only saline of genes related to liver detoxification and (SF) was administered. For the induction of elimination of xenobiotics and endobiotics cholestasis (BDL group), the bile duct was in the liver, is suppressed. On the contrary, doubly ligated at the hepatic hilum. This group it was reported that PXR activation is anti- was divided into three subgroups; the rats inflammatory in the liver and that it causes in the SPL1 group received spironolactone inhibition of NF-κB activation, as well as (Aldactone tablets, Ali Raif Pharmaceuticals, reducing the expression of inflammatory Istanbul, Turkey) (200 µmol/kg oral, dissolved cytokines such as TNF-α (5, 6). in 60 mM propylene glycol (10)) daily for Spironolactone (SPL) is a diuretic known 3 days, starting on the day of the operation. for its potent enzyme induction activity. It The rats in the SPL2 group received SPL (200 is widely used as a diuretic in patients with µmol/kg oral, dissolved in 60 mM propylene edema or ascites. Previous studies have shown glycol) daily for three days, starting 3 days that it induces MRP2 in the small intestine after the operation. The BDL group received and liver of rats (4, 7 and 8). Ethinylestradiol- 60 mM propylene glycol oral (the vehicle) for induced cholestasis has also been reported 3 days. At the end of the experiment, 18 h after to be reduced by SPL, possibly through the the last dose, the animals were decapitated induction of MRP2 (9). and blood and tissue (liver) samples were Since SPL was reported to increase collected. Tissue samples were stored in bile flow, and since it is widely used in the formalin for histological examination and at treatment of cirrhosis, in this study, we aimed -80 °C for biochemical evaluations. to investigate whether or not SPL, besides being a diuretic, has any other preventive Liver function tests effect in BDL-induced hepatitis development As the markers of hepatic function in rats, and whether induction of PXR and/or and tissue injury, the activities of alanine MRP2 plays a part in this effect aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline Experimental phosphatase (ALP) enzymes, and the total and direct bilirubin (TBIL, DBIL) concentrations Animals were studied with an automated analyzer Albino Wistar rats of both sexes weighing (Bayer OpeRA, Bayer Corp., Germany) using between 250-300 g were acclimatized to routine analysis kits (respectively REF 80027, laboratory conditions (+20 °C ± 2, 12 h REF 92025, REF80014, REF 80403, Biolabo light-dark cycle) for two weeks prior to the Europe S.A., Maizy, France). experiment, with free access to standard pellet chow and water. With respect to the laboratory Measurement of Serum Cytokines analyst and statistical analyst, they were Concentrations blinded to the groups and treatments allocated Serum NF-ĸB, TNF-α and IL-6 to the rats. This study was conducted with concentrations quantified according to the consent of the Animal Ethics Committee manufacturer's instructions and guidelines 36 Effects of Spironolactone in BDL-hepatitis using rat-specific commercially available Histopathological Examination ELISA test kits (BioSource Europe S.A.; The tissues were washed in tap water for at Nivelles, Belgium). least 3 h or 1 night after being taken into 10% formalin, and dehydration was performed with Determination of tissue Myeloperoxidase increasing alcohol concentrations (15 min (MPO) activity with 70% alcohol, 15 min with 90% alcohol, Determination of the myeloperoxidase 30 min with 96% alcohol, twice for 30 min (MPO) level in the tissue was made by the with 100% alcohol, and twice for 30 min with Hillegeas method (11). Immediately after 100% toluene). Subsequently, they were kept decapitation, the extracted tissues were washed in paraffin blocks at 60 °C for 1 night and the with saline to remove blood and debris, then next day, the tissue was embedded in paraffin dried with filter paper and weighed. The blocks. After blocking, sections of 5-6 mm tissue samples were homogenized in 10 thickness were obtained from the tissues and vol of ice-cold potassium phosphate buffer placed on the slide and left in toluene for 2 h (50 mM/L K2HPO4 (pH 6) containing for separating from paraffin, then reduced to hexadecyltrimethylammonium bromide water with reduced concentrations of alcohol (HETAB; 0.5%, w/v). The homogenate was (2 min with 100% alcohol, 2 min with 90% centrifuged at 30,000g for 10 min at 4 °C, and alcohol, 2 min with 70% alcohol) and left in the supernatant was discarded. The pellet was distilled water, treated with hematoxylin for then rehomogenized with an equivalent volume 15 min, then left for purpling for 10 min in tap of 50 mmol//L K2HPO4 containing 0.5% (w/v) water. After applying distilled water with eosin HETAB (Sigma-Aldrich, St. Louis, USA) and for another 5 min, dehydration was carried out 10 mmol/L ethylenediaminetetraaceticacid with increasing alcohol concentrations (2 min (EDTA, Sigma). MPO activity was assessed with 70% alcohol, 2 min with 90% alcohol,
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