Effects of nimesulide and its reduced metabolite on mitochondria

Abstract

1 We investigated the e ects of nimesulide, a recently developed non-steroidal anti-in¯ammatory drug, and of a metabolite resulting from reduction of the nitro group to an amine derivative, on succinate-energized isolated rat liver mitochondria incubated in the absence or presence of 20 mM Ca 2+ , 1 mM cyclosporin A (CsA) or 5 mM ruthenium red. 2 Nimesulide uncoupled mitochondria through a protonophoretic mechanism and oxidized mitochondrial NAD(P)H, both e ects presenting an EC 50 of approximately 5 mM. 3 Within the same concentration range nimesulide induced mitochondrial Ca 2+ e ux in a partly ruthenium red-sensitive manner, and induced mitochondrial permeability transition (MPT) when ruthenium red was added after Ca 2+ uptake by mitochondria. Nimesulide induced MPT even in deenergized mitochondria incubated with 0.5 mM Ca 2+ . 4 Both Ca 2+ e ux and MPT were prevented to a similar extent by CsA, Mg 2+ , ADP, ATP and butylhydroxytoluene, whereas dithiothreitol and N-ethylmaleimide, which markedly prevented MPT, had only a partial or no e ect on Ca 2+ e ux, respectively. 5 The reduction of the nitro group of nimesulide to an amine derivative completely suppressed the above mitochondrial responses, indicating that the nitro group determines both the protonophoretic and NAD(P)H oxidant properties of the drug. 6 The nimesulide reduction product demonstrated a partial protective e ect against accumulation of reactive oxygen species derived from mitochondria under conditions of oxidative stress like those resulting from the presence of t-butyl hydroperoxide. 7 The main conclusion is that nimesulide, on account of its nitro group, acts as a potent protonophoretic uncoupler and NAD(P)H oxidant on isolated rat liver mitochondria, inducing Ca 2+ e ux or MPT within a concentration range which can be reached in vivo, thus presenting the potential ability to interfere with the energy and Ca 2+ homeostasis in the liver cell.

Hyaluronic acid–nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo

“…67 In addition, NiNH 2 can completely suppress the uncoupling and NAD(P)H oxidant effects on mitochondria. 68,69 In this study, the nitro group of nimesulide was reduced to amine first and then grafted onto HA, suggesting that HA-nimesulide might reduce the liver toxicity effects of free nimesulide.…”

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

“…The mitochondrial effects of nimesulide have been previously assessed in isolated liver mitochondria and isolated rat hepatocytes (Moreno-Sanchez et al, 1999;Mingatto et al, 2000Mingatto et al, , 2002. Nimesulide behaves like a protonophoric weak acid and uncouples mitochondrial respiration (MorenoSanchez et al, 1999).…”

“…Nimesulide behaves like a protonophoric weak acid and uncouples mitochondrial respiration (MorenoSanchez et al, 1999). Although this effect may be mediated by the sulfonamide moiety of nimesulide (see Discussion), it has been ascribed instead to the nitro group on the basis that the amine derivative formed by the nitro reduction of nimesulide did not uncouple mitochondrial respiration (Mingatto et al, 2000(Mingatto et al, , 2002. Nimesulide was also shown to induce ATP depletion and cell death in isolated hepatocytes incubated for 90 min with a low concentration of albumin (1 mg/ml) (Mingatto et al, 2002).…”

Antioxidative burst and hepatoprotective effects of ethanol root extract ofHippocratea africanaagainst paracetamol-induced liver injury

“…Induction of cytochrome and depletion of glutathione are the major predisposing factors to liver injury (Gupta et al, 2006). The experimental evidence suggests that during metabolism of this type of drug, different reactive metabolites are produced that covalently modify proteins (Bernareggi, 1998), impose oxidative stress (Berson et al, 1991;Ritter & Malejka-Giganti, 1998) and cause mitochondrial injury (Mingatto et al, 2000). Damage to the structural integrity of liver is reflected by an increase in the levels of serum transaminases AST, ALT and ALP, because they are cytoplasmic in location and are released into the circulation after cellular damage.…”