sq-23377 and Chemical-and-Drug-Induced-Liver-Injury

Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo.

Topics: Acetaminophen; Animals; Antioxidants; Carotenoids; Catalase; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Ionomycin; Liver; Lycopene; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species

The alterations of mitochondrial membrane potential during the development of irreversible cell damage were investigated by measuring rhodamine-123 uptake and distribution in primary cultures as well as in suspensions of rat hepatocytes exposed to different toxic agents. Direct and indirect mechanisms of mitochondrial damage have been identified and a role for Ca2+ in the development of this type of injury by selected compounds was assessed by using extracellular as well as intracellular Ca2+ chelators. In addition, mitochondrial uncoupling by carbonylcyanide-m-chloro-phenylhydrazone (CCCP) resulted in a marked depletion of cellular ATP that was followed by an increase in cytosolic Ca2+ concentration, immediately preceding cell death. These results support the existence of a close relationship linking, in a sort of reverberating circuit, the occurrence of mitochondrial dysfunction and the alterations in cellular Ca2+ homeostasis during hepatocyte injury.

Topics: Adenosine Triphosphate; Animals; Calcium; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cells, Cultured; Chemical and Drug Induced Liver Injury; Fluorescent Dyes; Ionomycin; Kinetics; Liver Diseases; Membrane Potentials; Mitochondria, Liver; Rats; Rats, Inbred Strains; Rhodamine 123; Rhodamines; Vitamin K