Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death

Hickey, Eileen; Raje, R. R.; Reid, Vincent E.; Gross, Stephen; Ray, Sidhartha D.

doi:10.1016/s0891-5849(01)00560-3

Cited by 186 publications

(114 citation statements)

References 55 publications

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“…3). DCF has been shown to induce nephrotoxicity in ICR mice evidenced by a 2.5-fold increase in BUN concentrations 24 hours after an oral 100 mg/kg dose (Hickey et al, 2001). The finding in ICR mice likely reflects that strain's higher sensitivity to renal injury, because C57BL/6 mice ( Fig.…”

Section: Discussionmentioning

confidence: 92%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistanceassociated proteins (Mrp). The importance of Mrp2 during DCFinduced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.

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Section: Discussionmentioning

confidence: 92%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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“…The significant increase in level of serum and renal TNF-α, NO and TBARS in diclofenac-treated groups indicates ongoing peroxidative stress and compromised antioxidant defense mechanisms. The mechanism of diclofenac-induced mitochondrial injury seems to involve generation of ROS, causing oxidative stress to renal tissue as proposed by Hickey et al [38]. The underlying mechanisms to produce oxidative stress by the effect of NSAIDs have been suggested to be based on the releasing of NSAID radicals, which in turn can oxidize GSH and NAD(P)H. NSAID radicals can undergo redox cycling.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies indicate that ROS can affect the functional as well as structural integrity of cell membrane and organelles [59] But according to Hickey et al [38] DCLF suppress cellular genomic repair capability, and activated kidney endonuclease to produce damage.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Cranberry Extracts against Oxidative Stress and DNA Damage Induced by Diclofenac Sodium in Kidney of Male Albino Rate

Hassan¹,

Sabry²,

Hussein³

2017

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This work aimed to find the effect of cranberry extract (75 and 150 mg/kg•b•w) and vit. C (1 g/kg•b•w orally) on renal toxicity induced by Diclofenac sodium in male albino rats. Treated rats with diclofenac sodium with a concentration 150 mg/kg•b•w, expressed a significant increase in several parameters includes, plasma total cholesterol, LDL-cholesterol, and triglyceride as well as renal nitric oxide (NO), tumor necrosis factor-alfa (TNF-α) and TBARS. In addition, a significant reduction in renal superoxide dismutase (SOD), GSH, catalase (CAT) and plasma HDL. The present results explain that, using cranberry extract and vit. C resulted in increasing the level of GSH, CAT and SOD as well as gene expression of renal SOD, CAT and IL-22 and reduce the level of TBARs significantly which led to preventing renal tissue damage. Our results also revealed that cranberry extract can protect DNA from damage as obtained from comet essay. TM-U was elevated in DCLF treated group when compared with normal. However cranberry extract was able to reduce this elevation in dose dependant manner. Histological features in H&E taken to different groups also mirrors this findings. DCLF causes many changes in renal tissue include infiltration by inflammatory cells, attenuated glomeruli, apoptosis in tubular epithelia. Keywords

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“…However, with the necropsies undertaken showing the common finding of diffuse visceral gout and proximal convoluted tubular damage, it has been concluded that kidneys or its supportive vascular system are the site of toxicity (Meteyer et al, 2005, Oaks et al, 2004and Swan et al, 2006b). The latter is not completely unexpected as diclofenac is known to be a nephrotoxic agent at higher doses in people (Hickey et al, 2001). Meteyer et al (2005) proposed the inhibition of renal prostaglandins (PG) and subsequent closure of the renal portal valves as causes of severe renal ischemia and nephrotoxicity.…”

Section: Introductionmentioning

confidence: 95%

Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction

Naidoo

Swan

2009

Comparative Biochemistry and Physiology Part C: Toxicology &

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Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death

Cited by 186 publications

References 55 publications

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Protective Effect of Cranberry Extracts against Oxidative Stress and DNA Damage Induced by Diclofenac Sodium in Kidney of Male Albino Rate

Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction

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