comparison of hepatocyte cytotoxic mechanisms for docetaxel and PLGA-docetaxel nanoparticls

Docetaxel [DTX] is one of the most widely used drugs in oncology due to its high efficacy against several cancers. Though, its routine clinical administration, formulated in tween 80, causes serious side effects. Polylactide-co-glycolide [PLGA], biodegradable polyester synthesized and approved for human use, is employed to overcome these problems. In this investigation, we compare the cytotoxic mechanisms of DTX and PLGA-DTX in isolated rat hepatocytes. Cytotoxicity of DTX and PLGA-DTX were associated with reactive oxygen species formation, activation of caspases cascade, collapse of mitochondrial membrane potential [MMP], lysosomal membrane leakiness and ATP depletion. Our results also showed that CYP2E1 is involved in the oxidative stress cytotoxicity mechanism and both drugs are detoxified via phase II metabolic methylation. Furthermore, we concluded that PLGA-DTX is bioactivated by GSH. It could also potentiate hepatocyte toxicity through a mitochondrial/lysosomal toxic cross-talk. In addition to these observed differences, it is likely that mode of hepatocyte membrane penetration is different between these compounds

Ichthyotoxic cochlodinium polykrikoides induces mitochondrial mediated oxidative stress and apoptosis in rat liver hepatocytes

In this research, we investigated the cytotoxic mechanisms of CochlodiniumpolykrikoidescQ/ lysate on isolated rat liver hepatocytes.This micro algae is responsible for a severe and widespread harmful algal bloom in the Persian Gulf and Gulf of Oman [2008-2009]. Isolated hepatocytes were obtained by collagenase perfiision of Sprague-Dawley rat liver.According to our results, incubation of algal lysate with isolated rat hepatocytescaused hepatocyte membrane lysis, reactive oxygen species [ROS] formation, glutathione depletion, collapse of mitochondrial membrane potential,ATP depletion and increase in ADP/ATP ratio, cytochrome c release in to the hepatocyte cytosol,activation of caspase-3 [final mediator of apoptosis] and appearance of apoptosis phenotype. On the other hand, pre-treatment of antioxidants [a-tocopherol succinate and BHT], radical scavengers [mannitol and DMSO], mitochondrial permeability transition [MPT] pore sealing agents [cyclosporine A, carnitine and trifluoperazine], NADPH P450 reductase inhibitor [Diphenyliodonium chloride], CYP2E1 inhibitors [Phenylimidazole and 4-Methylpyrazole] and ATP generators [L-glutamine, Fructose and Xylitol]inhibitedcaspase-3 activation and cell death in algal lysate treated hepatocytes.Our data also confirmed that algal lysate activates apoptosis signaling via oxidative stress and mitochondrial pathway. Thus, ROS formation caused by the lysate exposure could directly be involved in mitochondrial MPT pore opening and activation of caspase-3 leading to C.polykrikoides lysateinduced apoptosis on rat hepatocytes. These findings contribute to a better understanding QfC.polykrikoides-toxic effects on mammalian liver cells