title: Luteolin modulates expression of drug-metabolizing enzymes through the AhR and Nrf2 pathways in hepatic cells.
abstract: Drugs, xenobiotics including environmental pollutants, and certain food components modulate expression of drug-metabolizing enzymes. An aryl hydrocarbon receptor (AhR) possesses possible expression of phase I and phase II enzymes directly by binding of its ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and indirectly by regulating expression of nuclear factor-erythroid-2-related factor 2 (Nrf2). Previous our result demonstrated that luteolin, a natural flavonoid existing in vegetables and herbs, competed the binding of TCDD to AhR. In the present study, we investigated the effect of luteolin on the expression of drug-metabolizing enzymes through the AhR and Nrf2 pathways. Luteolin inhibited TCDD-induced protein expression of phase I enzyme cytochrome P450 1A1 (CYP1A1), phase II enzymes
  quinone oxidoreductase-1 (NQO1) and glutathione-S-transferase P1 (GSTP1) in HepG2, Hepa1c1c7 and RL-34 cells in a dose-dependent manner. Luteolin suppressed TCDD- and tert-butylhydroquinone-induced Nrf2 protein by decreasing its stability in HepG2 cells. In tert-butylhydroquinone treated cells, luteolin dose-dependently inhibited NQO1, GSTP1 and aldo-keto reductases (AKRs). Of these, protein expression of CYP1A1 and GSTP1 was mainly dominated by the AhR pathway, while that of NQO1 and AKRs was by the Nrf2 pathway. In conclusion, luteolin inhibits expression of phase I and phase II drug-metabolizing enzymes by modulating the AhR and Nrf2 pathways.
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Tianshun
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Songyan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Kiyonari
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan. Electronic address: ashida@kobe-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ashida
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D047311:Luteolin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017931:DNA Primers; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D047311:Luteolin
keywords: Aryl hydrocarbon receptor; Drug-metabolizing enzymes; Luteolin; Nuclear factor-erythroid-2-related factor 2