title: Curcumin inhibits activation of TRPM2 channels in rat hepatocytes.
abstract: Oxidative stress is a hallmark of many liver diseases including viral and drug-induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca(2+) homeostasis, resulting in a sustained elevation of the free cytosolic Ca(2+) concentration ([Ca(2+)]c) in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca(2+) entry through Transient Receptor Potential Melastatin 2 (TRPM2) channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5µM curcumin in the incubation medium prevented the H2O2- and paracetamol-induced [Ca(2+)]c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC50 of approximately 50nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels.
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Kheradpezhouh
authors.affiliation: Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, SA 5001, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Barritt
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia; Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: G Y
authors.initials: GY
authors.lastname: Rychkov
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; C557080:Trpm2 protein, rat; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D003474:Curcumin
keywords: Curcumin; Hepatocytes; Oxidative stress; Patch clamping; TRPM2 channel