title: Protective effects of ferulic acid and related polyphenols against glyoxal- or methylglyoxal-induced cytotoxicity and oxidative stress in isolated rat hepatocytes.
abstract: Glyoxal (GO) and methylglyoxal (MGO) cause protein and nucleic acid carbonylation and oxidative stress by forming reactive oxygen and carbonyl species which have been associated with toxic effects that may contribute to cardiovascular disease, complications associated with diabetes mellitus, Alzheimer's and Parkinson's disease. GO and MGO can be formed through oxidation of commonly used reducing sugars e.g., fructose under chronic hyperglycemic conditions. GO and MGO form advanced glycation end products which lead to an increased potential for developing inflammatory diseases. In the current study, we have investigated the protective effects of ferulic acid and related polyphenols e.g., caffeic acid, p-coumaric acid, methyl ferulate, ethyl ferulate, and ferulaldehyde on GO- or MGO-induced cytotoxicity and oxidative stress (ROS formation, protein carbonylation and mitochondrial membrane potential maintenance) in freshly isolated rat hepatocytes. To investigate and compare the protective effects of ferulic acid and related polyphenols against GO- or MGO-induced toxicity, five hepatocyte models were used: (a) control hepatocytes, (b) GSH-depleted hepatocytes, (c) catalase-inhibited hepatocytes, (d) aldehyde dehydrogenase (ALDH2)-inhibited hepatocytes, and (e) hepatocyte inflammation system (a non-toxic H2O2-generating system). All of the polyphenols tested significantly decreased GO- or MGO-induced cytotoxicity, ROS formation and improved mitochondrial membrane potential in these models. The rank order of their effectiveness was caffeic acid∼ferulaldehyde>ferulic acid>ethyl ferulate>methyl ferulate>p-coumaric acid. Ferulic acid was found to decrease protein carbonylation in GSH-depleted hepatocytes. This study suggests that ferulic acid and related polyphenols can be used therapeutically to inhibit or decrease GO- or MGO-induced hepatotoxicity.
authors.affiliation: Graduate Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: Abdullah Al
authors.initials: AA
authors.lastname: Maruf
authors.affiliation: Graduate Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: HoYin
authors.initials: H
authors.lastname: Lip
authors.affiliation: Graduate Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: Horace
authors.initials: H
authors.lastname: Wong
authors.affiliation: Graduate Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Canada. Electronic address: peter.obrien@utoronto.ca.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D003373:Coumaric Acids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006037:Glyoxal / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D059808:Polyphenols / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D003373:Coumaric Acids; D059808:Polyphenols; D017382:Reactive Oxygen Species; D006037:Glyoxal; C004999:ferulic acid; D006861:Hydrogen Peroxide; D000444:Aldehyde Dehydrogenase; D005978:Glutathione
keywords: Ferulic acid; Glyoxal; Isolated rat hepatocytes; Methylglyoxal; Oxidative stress; Polyphenols