title: Arsenic trioxide induced indirect and direct inhibition of glutathione reductase leads to apoptosis in rat hepatocytes.
abstract: Glutathione reductase (GR) is an essential enzyme which maintains the reduced state of a cell. Therefore GR malfunction is closely associated with several disorders related to oxidative damage. The present study reports toxic manifestation of arsenic trioxide in respect of GR leading to apoptosis. Isolated rat hepatocytes exposed to arsenic trioxide were analyzed for GR expression and activity. Arsenic resulted in a time dependent inhibition of GR mediated by the superoxide anion. The cellular demand of functional enzyme is achieved by concomitant rise in gene expression. However, direct inhibition of GR by arsenic trioxide was also evident. Furthermore, arsenic induced free radical mediated inhibition of GR was found to be partially uncompetitive and associated with time dependent decrease in the substrate binding rate. Externalization of phosphatidylserine, nuclear degradation, apoptosis inducing factor leakage, apoptosome formation, caspase activation, DNA damage and break down of PARP suggest consequential induction of apoptosis due to inhibition of GR. The implication of GR was further established from the reduced rate of caspase activation in the arsenic trioxide treated cell, supplemented with complete and incomplete enzyme systems.
authors.affiliation: Environmental Toxicology Laboratory, Department of Zoology, Centre for Advanced Studies, Visva-Bharati (A Central University), Santiniketan, 731235, India.
authors.forename: Atish
authors.initials: A
authors.lastname: Ray
authors.forename: Sarmishtha
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Sandip
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Shelley
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D007700:Kinetics; D008297:Male; D010084:Oxidation-Reduction; D010087:Oxides / Q000633:toxicity*; D017207:Rats, Sprague-Dawley
chemical_list: D001152:Arsenicals; D004785:Environmental Pollutants; D005609:Free Radicals; D010087:Oxides; D005980:Glutathione Reductase; D000077237:Arsenic Trioxide; D019803:Glutathione Disulfide