title: Induction of glutathione synthesis and heme oxygenase 1 by the flavonoids butein and phloretin is mediated through the ERK/Nrf2 pathway and protects against oxidative stress.
abstract: Butein and phloretin are chalcones that are members of the flavonoid family of polyphenols. Flavonoids have well-known antioxidant and anti-inflammatory activities. In rat primary hepatocytes, we examined whether butein and phloretin affect tert-butylhydroperoxide (tBHP)-induced oxidative damage and the possible mechanism(s) involved. Treatment with butein and phloretin markedly attenuated tBHP-induced peroxide formation, and this amelioration was reversed by l-buthionine-S-sulfoximine [a glutamate cysteine ligase (GCL) inhibitor] and zinc protoporphyrin [a heme oxygenase 1 (HO-1) inhibitor]. Butein and phloretin induced both HO-1 and GCL protein and mRNA expression and increased intracellular glutathione (GSH) and total GSH content. Butein treatment activated the ERK1/2 signaling pathway and increased Nrf2 nuclear translocation, Nrf2 nuclear protein-DNA binding activity, and ARE-luciferase reporter activity. The roles of the ERK signaling pathway and Nrf2 in butein-induced HO-1 and GCL catalytic subunit (GCLC) expression were determined by using RNA interference directed against ERK2 and Nrf2. Both siERK2 and siNrf2 abolished butein-induced HO-1 and GCLC protein expression. These results suggest the involvement of ERK2 and Nrf2 in the induction of HO-1 and GCLC by butein. In an animal study, phloretin was shown to increase GSH content and HO-1 expression in rat liver and decrease carbon tetrachloride-induced hepatotoxicity. In conclusion, we demonstrate that butein and phloretin up-regulate HO-1 and GCL expression through the ERK2/Nrf2 pathway and protect hepatocytes against oxidative stress.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Ya-Chen
authors.initials: YC
authors.lastname: Yang
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.forename: Ai-Hsuan
authors.initials: AH
authors.lastname: Lin
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Yeh
authors.forename: Hsien-Tsung
authors.initials: HT
authors.lastname: Yao
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010693:Phloretin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D047188:Chalcones; D051267:NF-E2-Related Factor 2; C040918:butein; D020122:tert-Butylhydroperoxide; D002251:Carbon Tetrachloride; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D010693:Phloretin