Troglitazone-induced intracellular oxidative stress in rat hepatoma cells: a flow cytometric assessment. 2003

Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. padma.k.narayanan@gsk.com

BACKGROUND Troglitazone (TRO), a thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma agonist, was recently withdrawn from the market because of rare but serious hepatotoxicity. Previous studies investigating the cytotoxicity of TRO in cultured rat hepatocytes have conjectured about the role of oxidative stress in TRO-induced hepatotoxicity. Therefore, we investigated whether TRO induces oxidative stress and, if so, the portion of the TRO molecule responsible for the induction of oxidative stress. METHODS Novikoff rat hepatoma (N1S1) cells were incubated with TRO, troglitazone quinone (TQ), thiazolidinedione-phenoxyacetic acid (TD-PAA) or rosiglitazone (RSG). Membrane peroxidation, intracellular glutathione (GSH) content, and cellular viability were monitored simultaneously by multiparameter flow cytometry. RESULTS TRO and TQ increased membrane peroxidation, decreased intracellular GSH, and decreased cell viability in a concentration-dependent manner. In contrast, TD-PAA and RSG neither increased membrane peroxidation nor induced loss of cell viability. In addition, TRO caused a concentration-dependent increase in intracellular superoxide generation accompanied by a collapse in mitochondrial membrane potential. CONCLUSIONS Multiparameter flow cytometric evaluation of N1S1 cells indicated that the chromane ring of TRO, rather than the TZD moiety, may be responsible for oxidative stress and suggested that a direct effect on mitochondrial physiology may play a role in TRO-mediated hepatotoxicity.

UI MeSH Term Description Entries
D008564 Membrane Potentials The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization). Resting Potentials,Transmembrane Potentials,Delta Psi,Resting Membrane Potential,Transmembrane Electrical Potential Difference,Transmembrane Potential Difference,Difference, Transmembrane Potential,Differences, Transmembrane Potential,Membrane Potential,Membrane Potential, Resting,Membrane Potentials, Resting,Potential Difference, Transmembrane,Potential Differences, Transmembrane,Potential, Membrane,Potential, Resting,Potential, Transmembrane,Potentials, Membrane,Potentials, Resting,Potentials, Transmembrane,Resting Membrane Potentials,Resting Potential,Transmembrane Potential,Transmembrane Potential Differences
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D008956 Models, Chemical Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment. Chemical Models,Chemical Model,Model, Chemical
D010100 Oxygen An element with atomic symbol O, atomic number 8, and atomic weight [15.99903; 15.99977]. It is the most abundant element on earth and essential for respiration. Dioxygen,Oxygen-16,Oxygen 16
D010617 Phenanthridines
D011419 Propidium Quaternary ammonium analog of ethidium; an intercalating dye with a specific affinity to certain forms of DNA and, used as diiodide, to separate them in density gradients; also forms fluorescent complexes with cholinesterase which it inhibits. Propidium Diiodide,Propidium Iodide,Diiodide, Propidium,Iodide, Propidium
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D002839 Chromans Benzopyrans saturated in the 2 and 3 positions. Dihydrobenzopyrans
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response

Related Publications

Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
August 1996, Hepatology (Baltimore, Md.),
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
December 1998, European cytokine network,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
August 1993, Cancer letters,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
September 2017, Scientific reports,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
January 2014, Nutrition and cancer,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
July 1987, The American journal of physiology,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
July 1997, The Journal of physiology,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
May 1999, International journal of cancer,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
November 1988, Journal of neuroscience methods,
Padma Kumar Narayanan, and Timothy Hart, and Fiona Elcock, and Cindy Zhang, and Laura Hahn, and David McFarland, and Lester Schwartz, and D Gwyn Morgan, and Peter Bugelski
August 1996, Japanese journal of pharmacology,
Copied contents to your clipboard!