Sulfasalazine induces mitochondrial dysfunction and renal injury (original) (raw)
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Lipid peroxidation and antioxidant status in kidney and liver of rats treated with sulfasalazine
Toxicology, 2009
Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD). In this study, the changes in endogenous antioxidant capacity and oxidative damage in liver and kidney of SASP-treated rats were investigated. Adult male Sprague-Dawley rats were orally given 0, 300, or 600 mg SASP/kg body weight for 14 days. One half of the animals in each group remained 14 additional days without SASP treatment. At the end of the experimental period, rats were euthanized and liver and kidney were removed. In both organs, the following stress markers were determined: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-Stransferase (GST), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid-reactive substances (TBARS). Moreover, histological examination of kidneys showed phagolysosomes after 14 days of SASP withdrawal. A dropsical degeneration was also observed in renal tissue. Oral SASP administration induced a significant increase in TBARS levels in both liver and kidney. After 2 weeks without SASP administration, a recovery of these levels was noted. SOD activity was significantly reduced, while CAT activity significantly increased at 600 mg SASP/(kg day). In kidney, GPx activity significantly increased, while GST activity and GSH levels were significantly reduced at 600 mg SASP/(kg day). These results suggest that in male rats, oxidative damage can be a mechanism for nephro-and hepatotoxicity related with SASP treatment.
Sulfasalazine reduces inflammatory renal injury in unilateral ureteral obstruction
Pediatric Nephrology, 2007
The purpose of this study was to test whether sulfasalazine has a protective action against interstitial inflammation and the development of renal fibrosis in obstructive nephropathy. Female rats were subjected to a sham (n = 10) or unilateral ureteral obstruction (UUO, n = 30). UUO was induced in rats by ligating the left ureter. Three days after operation, rats subjected to UUO were randomized to receive tretment with either sulfasalazine (100 mg/kg) or vehicle every day for the last 7 days of the experiment. At 10 days following UUO, the obstructed kidney exhibited tubulointerstitial injury and leukocyte infiltration (mainly monocytes) that were associated with high levels of reactive oxygen species, cytokines, transforming growth factor (TGF)-β1, myeloperoxidase (MPO), and lipid peroxidation. Ten days after UUO, the obstructed kidney was also associated with increased nuclear factor kappa beta (NF-κβ) expression in saline-treated rats. Compared with sham-operated rats, UUO rat kidneys showed lower concentrations of antioxidant enzymes in the obstructed kidney tissue. All of these changes were significantly attenuated by treatment with sulfasalazine in the obstructed kidney. Sulfasalazine protected against the renal interstitial inflammation and tissue damage elicited by ureteral occlusion. Inhibition of the NF-κβ-dependent pathway and inflammatory response and oxidative stress inhibition is likely to be involved in the beneficial effects of sulfasalazine.
Current Therapeutic Research, 2009
BACKGROUND: Sulfasalazine, an inhibitor of cyclooxygenase, 5-lipoxygenase, and nuclear factor KB (NF-KB), has been found to alleviate oxidative damage, proinflammatory cytokine production, bile-duct proliferation, neutrophil infiltration, and fibrosis. Therefore, it may have a potential effect in attenuating lipid peroxidation and histologic liver damage in patients with biliary obstruction and biliary obstruction with sepsis.
Inhibition of neutrophil degranulation and superoxide production by sulfasalazine
Biochemical Pharmacology, 1987
Sulfasalazine is a potent inhibitor of superoxide production and granule enzyme release by stimulated neutrophils, and modulation of these responses may contribute to its anti-inflammatory properties. It is a composite drug consisting of 5-aminosalicylic acid and sulfapyridine joined through an azo linkage. To investigate which functional groups on the molecule are active against neutrophil responses, 5-aminosalicylic acid, sulfapyridine and olsalazine were added to cells stimulated with fMet-Leu-Phe or immune complexes. The inhibitory effects of sulfasalazine on superoxide production, degranulation and neutrophil-mediated collagen degradation were closely mimicked by olsalazine, with the other two compounds having little effect on either function. Thus the azo link appears to be the important structural feature of sulfasalazine that affects neutrophil responses. This suggests that sulfasalazine could be anti-inflammatory in its own right rather than just acting as a source of 5aminosalicylic acid. Our findings are also a favourable indication for olsalazine (Dipentum), which is currently under trial as an anti-inflammatory agent.
Sulforaphane Attenuates Gentamicin-Induced Nephrotoxicity: Role of Mitochondrial Protection
Evidence-Based Complementary and Alternative Medicine, 2013
Sulforaphane (SFN), an isothiocyanate naturally occurring in Cruciferae, induces cytoprotection in several tissues. Its protective effect has been associated with its ability to induce cytoprotective enzymes through an Nrf2-dependent pathway. Gentamicin (GM) is a widely used antibiotic; nephrotoxicity is the main side effect of this compound. In this study, it was investigated if SFN is able to induce protection against GM-induced nephropathy both in renal epithelial LLC-PK1 cells in culture and in rats. SFN prevented GM-induced death and loss of mitochondrial membrane potential in LLC-PK1 cells. In addition, it attenuated GMinduced renal injury (proteinuria, increases in serum creatinine, in blood urea nitrogen, and in urinary excretion on N-acetyl--D-glucosaminidase, and decrease in creatinine clearance and in plasma glutathione peroxidase activity) and necrosis and apoptosis in rats. The apoptotic death was associated with enhanced active caspase-9. Caspase-8 was unchanged in all the studied groups. In addition, SFN was able to prevent GM-induced protein nitration and decrease in the activity of antioxidant enzymes catalase and glutathione peroxidase in renal cortex. In conclusion, the protective effect of SFN against GM-induced acute kidney injury could be associated with the preservation in mitochondrial function that would prevent the intrinsic apoptosis and nitrosative stress.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2018
Maleic acid (MA)-induced nephropathy that is characterized by proteinuria, glycosuria, phosphaturia and a deficient urinary acidification and concentration. Sulforaphane (SF) is an indirect antioxidant that shows nephroprotective effects. The aim of the present work was to test the pre-treatment with SF against the MA-induced nephropathy. Wistar rats (230-260 g) were separated in the following groups: control, MA (which received 400 mg/kg of MA), SF + MA (which received MA and 1 mg/kg of SF each day for four days) and SF (which only received SF). MA induced proteinuria, an increase in urinary excretion of N-acetyl-β-d-glucosaminidase, and a decrease in plasma glutathione peroxidase activity, renal blood flow, and oxygenation and perfusion of renal cortex. All these impairments correlated with higher levels of oxidative damage markers and exacerbated superoxide anion production on renal cortex. Moreover, MA impaired mitochondrial bioenergetics associated to complex I, mitochondrial m...
Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine
BioImpacts, 2016
Introduction: Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats. Methods: Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15 th , 24 h after the last dose of sulfasalazine. Results: Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage. Conclusion: Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects.
Digestive Diseases and Sciences, 1991
The in vitro antioxidant capacity of sulfasalazine (SASP), its metabolites (SP, 5-ASA), and olsalazine (OAZ), was studied by evaluating their effects on superoxide (02-') production. Assay systems were the xanthine-xanthine oxidase (X/XOD) reaction and phorbol myristate acetate (PMA)-activated polymorphonuclear leukocytes (PMNs), using the cytochrome c (cyt-c) reduction assay and a luminot-dependent chemiluminescence method. 5-ASA, SASP, and OAZ showed a dose-dependent scavenger effect in both 02-. generating systems, 5-ASA being the most powerful (>50% of inhibition in the PMNs system and >70% in the X/XOD system at 10 izM concentration). SP had an inhibitor.." effect only in the PMNs system but did not modify the activity of xanthine oxidase, thus excluding a scavenger action. These data suggest that the scavenger effect of 5-ASA, SASP, and OAZ may be an important mechanism of action.
Digestive Diseases and Sciences, 1991
The in vitro antioxidant capacity of sulfasalazine (SASP), its metabolites (SP,, and olsalazine (OAZ), was studied by evaluating their effects on superoxide (02-') production. Assay systems were the xanthine-xanthine oxidase (X/XOD) reaction and phorbol myristate acetate (PMA) -activated polymorphonuclear leukocytes (PMNs), using the cytochrome c (cyt-c) reduction assay and a luminot-dependent chemiluminescence method. 5-ASA, SASP, and OAZ showed a dose-dependent scavenger effect in both 02-. generating systems, 5-ASA being the most powerful (>50% of inhibition in the PMNs system and >70% in the X/XOD system at 10 izM concentration). SP had an inhibitor.." effect only in the PMNs system but did not modify the activity of xanthine oxidase, thus excluding a scavenger action. These data suggest that the scavenger effect of 5-ASA, SASP, and OAZ may be an important mechanism of action.