Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition.
Curcumin is a naturally occurring compound which is known to induce heme oxygenase 1 (HO-1), although the underlying mechanism has not been fully elucidated. This study investigates in detail the mechanism of HO-1 induction by curcumin in human hepatoma cells. There was increasing toxicity of curcumin at concentrations higher than 10 microM. Curcumin was found to induce HO-1 at doses of 10 to 25 microM. At both non-toxic and toxic doses, HO-1 induction was found to correlate with production of reactive oxygen species (ROS), suggesting a causative relationship. This was reinforced by the finding that pretreatment with the antioxidants N-acetylcysteine, vitamin E and catalase prevented HO-1 induction by curcumin. ROS production appeared to be mitochondrial in origin, and curcumin treatment resulted in depolarisation of the mitochondrial membrane potential. Nrf2 was induced by curcumin treatment, which was also partly ROS dependent. Using siRNA, Nrf2 was demonstrated to contribute to HO-1 induction. A panel of kinase inhibitors was used to examine the contribution of MAP kinases to the induction of HO-1 by curcumin. PKC and p38 MAPK activity are required for full induction of HO-1. Furthermore, curcumin also inhibited protein phosphatase activity. In conclusion, curcumin treatment results in ROS generation, activation of Nrf2 and MAP kinases and the inhibition of phosphatase activity in hepatocytes, and when curcumin is not administered in toxic doses, these multiple pathways converge to induce HO-1.
McNally
Stephen J
SJ
Tissue Injury and Repair Group, University of Edinburgh, Chancellor's Building, Little France, Edinburgh EH16 4SB, UK. stephen.mcnally@gmail.com
Harrison
Ewen M
EM
Ross
James A
JA
Garden
O James
OJ
Wigmore
Stephen J
SJ
D000975:Antioxidants / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D053148:Caspase 3; D053179:Caspase 7; D003474:Curcumin