title: Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture.
abstract: Usnic acid, a natural botanical product, is a constituent of some dietary supplements used for weight loss. It has been associated with clinical hepatotoxicity leading to liver failure in humans. The present study was undertaken for metabolism and toxicity evaluations of usnic acid in human hepatoblastoma HepG2 cells in culture. The cells were treated with the vehicle control and usnic acid at concentrations of 0-100 µm for 24 h at 37 °C in 5% CO2 . Following the treatment period, the cells were evaluated by biochemical and toxicogenomic endpoints of toxicity that included cytochrome P450 activity, cytotoxicity, oxidative stress, mitochondrial dysfunction and changes in pathway focused gene expression profiles. Usnic acid exposure resulted in increased P450 activity, cytotoxicity, oxidative stress and mitochondrial dysfunction in HepG2 cells. The pathway-focused gene expression analysis resulted in significantly altered expression of six genes out of a total of 84 genes examined. Of the six altered genes, three genes were up-regulated and three genes down-regulated. A marked up-regulation of one gene CCL21 associated with inflammation, one gene CCNC associated with proliferation and carcinogenesis and one gene UGT1A4 associated with metabolism as well as DNA damage and repair were observed in the usnic acid-treated cells compared with the vehicle control. Also a marked down-regulation of one gene CSF2 associated with inflammation and two genes (CYP7A1 and CYP2E1) associated with oxidative metabolic stress were observed in the usnic acid-treated cells compared with the control. The biomarkers used in this study demonstrate the toxicity of usnic acid in human hepatoblastoma HepG2 cells, suggesting an oxidative mechanism of action.
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, Laurel, MD 20708, USA. saura.sahu@fda.hhs.gov
authors.forename: Saura C
authors.initials: SC
authors.lastname: Sahu
authors.forename: Margaret
authors.initials: M
authors.lastname: Amankwa-Sakyi
authors.forename: Michael W
authors.initials: MW
authors.lastname: O'Donnell
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sprando
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism / Q000633:toxicity*; D019440:Anti-Obesity Agents / Q000378:metabolism / Q000633:toxicity*; D001572:Benzofurans / Q000378:metabolism / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000139:chemically induced; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D019440:Anti-Obesity Agents; D001572:Benzofurans; D015415:Biomarkers; C073339:usnic acid; D003577:Cytochrome P-450 Enzyme System