Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro

Tay, Vincent K.S.; Wang, Audrey S.; Leow, Koon Yeow; Ong, Michie M.K.; Wong, Kim Ping; Boelsterli, Urs A.

doi:10.1016/j.freeradbiomed.2005.05.013

Cited by 47 publications

(38 citation statements)

References 50 publications

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“…Nevertheless, these observations raised the possibility that nimesulide, through its capability to interfere with mitochondrial bioenergetics, has the ability to interfere with the energy production and Ca 2+ homeostasis in the liver cell, which in turn may constitute a relevant mechanism for the reported nimesulide-induced liver toxicity. Later, Tay et al [24] described that mitochondrial uncoupling induced by nimesulide is actually the trigger for induction of the MPT, which further leads to the generation of oxidative stress on isolated liver mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…It is now well recognized that the MPT is closely involved in cell death either by necrosis or by apoptosis [22,23,39,41]. In this regard, there is evidence that nimesulide can induce intracellular oxidative stress in vitro; its capability for redox cycling can produce superoxide anion and pose an oxidative stress [24,31,42]. Tay et al [24] demonstrated that the oxidative stress of isolated liver mitochondria exposed to nimesulide was a consequence of MPT pore opening.…”

Section: Discussionmentioning

confidence: 99%

“…Wistar rats (250-300 g) were used for the experiments and kept under controlled light (12 h/12 h day/night cycle), temperature (22)(23)(24) • C), and humidity (50%-60%) conditions, and with free access to water (pH 5.5) and food. The experiments reported here were carried out in accordance with the National Requirements for Vertebrate Animal Research and in accordance with the European Convention for the Protection of Animals Used for Experimental and Other Scientific Purposes.…”

Section: Animalsmentioning

confidence: 99%

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Unaltered hepatic oxidative phosphorylation and mitochondrial permeability transition in wistar rats treated with nimesulide: Relevance for nimesulide toxicity characterization

Moreno

Oliveira

Nova

et al. 2007

J Biochem & Molecular Tox

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Nonsteroidal anti-inflammatory drugs have been associated with hepatotoxicity in susceptible patients. One such example is nimesulide, a preferential cyclooxygenase 2-inhibitor, widely used for the treatment of inflammation and pain. It was suggested that nimesulide could exert its hepatotoxicity by altering hepatic mitochondrial function, which was demonstrated in vitro. The objective of this study was to verify whether liver mitochondria isolated from rats treated with doses of nimesulide well above therapeutic levels possessed decreased calcium tolerance and oxidative phosphorylation, which indicates in vivo nimesulide mitochondrial toxicity. Male and female rats received nimesulide or its vehicle twice daily, for 5 days, and were killed on the seventh day for the isolation of liver mitochondria. Mitochondrial respiration, transmembrane electric potential, and calcium tolerance were characterized in all experimental groups. Nimesulide had no effect on liver mitochondrial function. Indexes of mitochondrial integrity, calcium loading capacity, and oxidative phosphorylation efficiency were unchanged between liver mitochondria from treated and control animals. In the animals tested, no evidence of degraded mitochondrial function due to nimesulide administration could be found. The results corroborate the notion that despite recognized in vitro mitochondrial toxicity, nimesulide does not cause detectable mitochondrial dysfunction in Wistar rats, even when administered in much higher concentrations than those known to have anti-inflammatory effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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Unaltered hepatic oxidative phosphorylation and mitochondrial permeability transition in wistar rats treated with nimesulide: Relevance for nimesulide toxicity characterization

Moreno

Oliveira

Nova

et al. 2007

J Biochem & Molecular Tox

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“…8A). Cytochrome c egress from mitochondria blocks electron flow, causes over-reduction of upstream respiratory chain complexes, and increases mitochondrial ROS formation (Cai and Jones, 1998;Tay et al, 2005), which may trigger MPT in still unaffected mitochondria (Fig. 8A).…”

Section: Discussionmentioning

confidence: 99%

The Anti-Inflammatory Drug, Nimesulide (4-Nitro-2-phenoxymethane-sulfoanilide), Uncouples Mitochondria and Induces Mitochondrial Permeability Transition in Human Hepatoma Cells: Protection by Albumin

Berson

Cazanave²,

Descatoire³

et al. 2006

J Pharmacol Exp Ther

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Like other nonsteroidal anti-inflammatory drugs, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide) triggers hepatitis in a few recipients. Although nimesulide has been shown to uncouple mitochondrial respiration and cause hepatocyte necrosis in the absence of albumin, mechanisms for cell death are incompletely understood, and comparisons with human concentrations are difficult because 99% of nimesulide is albumin-bound. We studied the effects of nimesulide, with or without a physiological concentration of albumin, in isolated rat liver mitochondria or microsomes and in human hepatoma cells. Nimesulide did not undergo monoelectronic nitro reduction in microsomes. In mitochondria incubated without albumin, nimesulide (50 M) decreased the mitochondrial membrane potential (⌬ m ), increased basal respiration, and potentiated the mitochondrial permeability transition (MPT) triggered by calcium preloading. In HUH-7 cells incubated for 24 h without albumin, nimesulide (1 mM) decreased the ⌬ m and cell NAD(P)H and increased the glutathione disulfide/reduced glutathione ratio and cell peroxides; nimesulide triggered MPT, ATP depletion, high cell calcium, and caused mostly necrosis, with rare apoptotic cells. Coincubation with either cyclosporin A (an MPT inhibitor) or the combination of fructose-1,6-diphosphate (a glycolysis substrate) and oligomycin (an ATPase inhibitor) prevented the decrease in ⌬ m , ATP depletion, and cell death. A physiological concentration of albumin abolished the effects of nimesulide on isolated mitochondria or HUH-7 cells. In conclusion, the weak acid, nimesulide, uncouples mitochondria and triggers MPT and ATP depletion in isolated mitochondria or hepatoma cells incubated without albumin. However, in the presence of albumin, only a fraction of the drug enters cells or organelles, and uncoupling and toxicity are not observed.

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“…The possibility of direct toxic effect of nimesulide induced oxidative stress should also be considered. Nimesulide induced oxidative stress also mediated mitochondrial injury through uncoupling of oxidative phosphorylation in hepatocytes [18,19].…”

Section: Body Weight and Organ Weightmentioning

confidence: 99%

Nimesulide Induced Histopathological Changes in the Vas Deferens of Mice

Balaji

Subramanian²,

Gnanasundaram³

et al. 2013

JCDR

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Aim: Nimesulide, a preferential COX-2 inhibitor has 20 times more selectivity towards COX-2 than that of COX-1. COX-2 selective inhibitors cause frequent nephrotoxicity and hepatotoxicity following their usage. This proposes a physiological role of COX-2 in kidney and liver. Not much attention has been focused on the role of COX-2 with respect to reproduction especially in male reproduction, and the available information is scanty. Aims and Objectives:The present study aims to investigate the adverse effects of nimesulide in the vas deferens thereby indirectly assess the role of COX-2 in male reproductive tract. Material and Methods:Nimesulide was administered orally and the animals were maintained for different time periods prior to sacrifice. Results:The vas deferens of nimesulide treated mice showed extensive histopathological changes such as vacoulation and exfoliation of cells in the epithelial layer. Conclusion:Nimesulide administration leads to cytotoxic effects suggestive of apoptosis in the vas deferens of mice.

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Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro

Cited by 47 publications

References 50 publications

Unaltered hepatic oxidative phosphorylation and mitochondrial permeability transition in wistar rats treated with nimesulide: Relevance for nimesulide toxicity characterization

Unaltered hepatic oxidative phosphorylation and mitochondrial permeability transition in wistar rats treated with nimesulide: Relevance for nimesulide toxicity characterization

The Anti-Inflammatory Drug, Nimesulide (4-Nitro-2-phenoxymethane-sulfoanilide), Uncouples Mitochondria and Induces Mitochondrial Permeability Transition in Human Hepatoma Cells: Protection by Albumin

Nimesulide Induced Histopathological Changes in the Vas Deferens of Mice

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