title: Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes.
abstract: Chrysin, apigenin, and luteolin are flavones that differ in their number of hydroxyl groups in the B ring. In this study, we investigated the protection by chrysin, apigenin, and luteolin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress and the possible mechanisms involved in rat primary hepatocytes. Chrysin, apigenin, and luteolin dose-dependently up-regulated the protein expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase (GCL) catalytic (GCLC) and modifier subunit (GCLM) and increased the intracellular glutathione (GSH) content and the ratio of GSH to oxidized GSH. Among the flavones studied, chrysin showed the greatest induction of HO-1, GCLC, and GCLM protein expression and GSH content. Cellular reactive oxygen species production induced by tBHP was attenuated by pretreatment with chrysin, apigenin, and luteolin (P < .05), and this protection was reversed by the GCL inhibitor l-buthionine-S-sulfoximine and the HO-1 inhibitor zinc protoporphyrin. Chrysin, apigenin, and luteolin activated extracellular signal-regulated protein kinase 2 (ERK2), nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, nuclear Nrf2-antioxidant responsive element (ARE) binding activity, and ARE-dependent luciferase activity. Both ERK2 and Nrf2 siRNAs attenuated chrysin-induced HO-1, GCLC, and GCLM protein expression. Taken together, these results suggest that chrysin, apigenin, and luteolin inhibit tBHP-induced oxidative stress by up-regulating HO-1, GCLC, and GCLM gene transcription via the ERK2/Nrf2/ARE signaling pathways in rat primary hepatocytes.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC.
authors.forename: Chin-Shiu
authors.initials: CS
authors.lastname: Huang
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: Tsu-Shing
authors.initials: TS
authors.lastname: Wang
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D047311:Luteolin / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D015854:Up-Regulation / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C043561:chrysin; D047310:Apigenin; D020122:tert-Butylhydroperoxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D047311:Luteolin