title: Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity.
abstract: To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity.
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Jin
authors.affiliation: Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, Jiangxi, China.
authors.forename: Chunpeng
authors.initials: C
authors.lastname: Wan
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Li
authors.affiliation: The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Peng
authors.affiliation: Medical College, China Three Gorges University, Yichang, Hubei, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Huang
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D007529:Isoflavones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C007768:formononetin; D000082:Acetaminophen; D008315:Malondialdehyde; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione