The Critical Role of Mitochondrial Energetic Impairment in the Toxicity of Nimesulide to Hepatocytes

Abstract

We described the effects of nimesulide (N-[4-nitro-2-phenoxyphenyl]-methanesulfonamide) and its reduced metabolite in isolated rat hepatocytes. Nimesulide stimulated the succinatesupported state 4 respiration of mitochondria, indicating an uncoupling effect of the drug. Incubation of hepatocytes with nimesulide (0.1-1 mM) elicited a concentration-and time-dependent decrease in cell viability as assessed by lactate dehydrogenase leakage, a decrease of mitochondrial membrane potential as assessed by rhodamine 123 retention, and cell ATP depression. Nimesulide also decreased the levels of NAD(P)H and glutathione in hepatocytes, but the extent of the effects was less pronounced in relation to the energetic parameters; in addition, these effects did not imply the peroxidation of membrane lipids. The decrease in the viability of hepatocytes was prevented by fructose and, to a larger extent, by fructose plus oligomycin; it was stimulated by proadifen, a cytochrome P450 inhibitor. In contrast, the reduced metabolite of nimesulide did not present any of the effects observed for the parent drug. These results indicate that: 1) nimesulide causes injury to the isolated rat liver cells, 2) this effect is mainly mediated by impairment of ATP production by mitochondria due to uncoupling, and 3) on account of the activity of its nitro group, the parent drug by itself is the main factor responsible for its toxicity to the hepatocytes.

Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines

“…Dissipation of mitochondrial transmembrane potential is commonly associated with destabilization of the outer mitochondrial membrane, which leads to the release of cytochrome c and other proapoptotic mitochondrial proteins into the cytoplasmic compartment (14). In fact, cell survival depends on the maintenance of mitochondrial transmembrane potential because of its involvement in ATP synthesis and maintenance of oxidative phosphorylation (47,48). We observed that exposure to LfcinB resulted in a loss of mitochondrial transmembrane potential by Jurkat T leukemia cells.…”

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

“…64 The toxicity of nimesulide to hepatocytes has been previously observed 65,66 which is attributed mainly to the nitro group in its structure. 67 After reduction, NiNH 2 exhibits reduced toxicity than nimesulide in hepatocytes because nimesulide is a powerful protonophoretic uncoupler and NAD(P)H oxidant. 67 In addition, NiNH 2 can completely suppress the uncoupling and NAD(P)H oxidant effects on mitochondria.…”

“…67 After reduction, NiNH 2 exhibits reduced toxicity than nimesulide in hepatocytes because nimesulide is a powerful protonophoretic uncoupler and NAD(P)H oxidant. 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.…”

Citotoxicity of Fipronil on Hepatocytes Isolated from Rat and Effects of Its Biotransformation

“…Tang et al (2004) reported that the CYP3A4 isoform was primarily responsible for the hepatic metabolism of fipronil in humans. Therefore, to evaluate the effect of biotransformation on the toxicity of fipronil, some experiments were performed using hepatocytes that were isolated from the rats that were pretreated with proadifen, a classic inhibitor of cytochrome P450 (Anders and Mannering 1996;Bort et al 1998;Mingatto et al 2002;Somchit et al 2009). The interference of fipronil in the functioning of the mitochondrial electron transport chain in the isolated rat hepatocytes was monitored by measuring the oxygen consumption.…”