title: Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism.
abstract: Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity.
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Halley
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Speen
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Saunders
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Elizabeth A S
authors.initials: EA
authors.lastname: Brooke
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Nallasamy
authors.affiliation: Department of Pharmacology, Campbell University, School of Osteopathic Medicine, Buies Creek, NC 27506, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA yli@campbell.edu z_jia@uncg.edu.
authors.forename: Y Robert
authors.initials: YR
authors.lastname: Li
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA yli@campbell.edu z_jia@uncg.edu.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005978:Glutathione / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D020011:Protective Agents; D017392:Thiobarbituric Acid Reactive Substances; D009828:Oleanolic Acid; D000171:Acrolein; D005978:Glutathione
keywords: 12-dioxooleana-1; 2-cyano-3; 9-dien-28-imidazolide; HepG2 cells; acrolein; aldose reductase; cytoprotection; glutathione-S-transferases