A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells

• Published in: Archives of biochemistry and biophysics Vol. 663; pp. 151 - 159
• Main Authors: Kitakaze, Tomoya, Makiyama, Atsushi, Samukawa, Yumi, Jiang, Songyan, Yamashita, Yoko, Ashida, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2019
• Subjects: Aldehyde dehydrogenase 2; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Aldo-Keto Reductases - metabolism; Diet; Drug-metabolizing enzymes; Enzyme Activation; Enzymes - metabolism; Extracellular signal-regulated kinase 1/2; Glutathione Transferase - metabolism; Heme Oxygenase-1 - metabolism; Hep G2 Cells; Humans; Luteolin; Luteolin - administration & dosage; Luteolin - metabolism; MAP Kinase Signaling System; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - chemistry; NF-E2-Related Factor 2 - metabolism; Nuclear factor-erythroid-2-related factor 2; Phosphorylation; Ubiquitination; Aldehyde dehydrogenase 2; Luteolin; Drug-metabolizing enzymes; Extracellular signal-regulated kinase 1/2; Nuclear factor-erythroid-2-related factor 2
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2019.01.012

The flavon luteolin has various health-promoting activities including cardiovascular protection, anti-inflammatory activity and anticancer activity. A serum concentration of about 100 nM luteolin is reached by dietary habit. However, little is known about the function of luteolin over its physiological concentration range. In this study, we investigated whether a physiological concentration of luteolin could activate nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated expression of phase II drug-metabolizing enzymes in human hepatoma HepG2 cells. Interestingly, less than 1 nM of luteolin could induce phase II drug-metabolizing enzymes, such as GSTs, HO-1, and NQO1. Both 1 and 100 nM luteolin increased expression and activity of ALDH2, which metabolized toxic acetaldehyde into nontoxic acetic acid. Luteolin increased nuclear accumulation of Nrf2 and enhanced the ARE-binding complex through increasing the stability of the Nrf2 protein. Luteolin increased phosphorylation of Nrf2 at Ser40, and MEK inhibitors (U0126 and PD98059) canceled luteolin-induced phosphorylation of Nrf2. Furthermore, luteolin increased modified Keap1. In conclusion, a physiological concentration of luteolin induces the expression of phase II drug-metabolizing enzymes by enhancement of Nrf2 nuclear accumulation through MEK1/2-ERK1/2-mediated phosphorylation of Nrf2, increasing Nrf2 stability and inducing a conformational change of Keap1. •Physiological concentration of luteolin modulated the Nrf2 pathway.•Luteolin induced phosphorylation of Nrf2 at Ser40 via the ERK1/2 signaling pathway.•Luteolin increased expression and activity of ALDH2.