Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture

• Published in: Journal of applied toxicology Vol. 32; no. 9; pp. 722 - 730
• Main Authors: Sahu, Saura C., Amankwa-Sakyi, Margaret, O'Donnell Jr, Michael W., Sprando, Robert L.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-09-2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Anti-Infective Agents - metabolism; Anti-Infective Agents - toxicity; Anti-Obesity Agents - metabolism; Anti-Obesity Agents - toxicity; Benzofurans - metabolism; Benzofurans - toxicity; Biological and medical sciences; Biomarkers - metabolism; Cell culture; Cell Survival - drug effects; Cytochrome P-450 Enzyme System - metabolism; Cytotoxicity; dietary supplement; Dietary supplements; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression - drug effects; gene expression profiles; Genes; Hep G2 Cells; Hepatoblastoma - drug therapy; Hepatoblastoma - genetics; Hepatoblastoma - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; hepatotoxicity; HepG2 cells; Human; Humans; Liver; liver cells; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; liver toxicity; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Mitochondria, Liver - drug effects; Mitochondrial Diseases - chemically induced; Other diseases. Semiology; Oxidative Stress - drug effects; Oxidative Stress - genetics; Stresses; Toxicity; Toxicology; usnic acid; Vehicles; Weight control; Weight loss; USA; Cell culture; Toxicity; dietary supplement; Liver; Hepatic disease; HepG2 cells; Fungi; Hepatocyte; Supplementation; Hepatoblastoma; Food supplement; Human; Digestive system; Exposure; Malignant tumor; In vitro; usnic acid; Gene expression profile; Cell line; liver toxicity; hepatotoxicity; gene expression profiles; liver cells; Digestive diseases; Lichenes; Cancer
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.1721

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. Published 2011. This article is a US Government work and is in the public domain in the USA.
Usnic acid is a constituent of some dietary supplements used for weight loss. Its exposure resulted in increased P450 activity, cytotoxicity, oxidative stress and mitochondrial dysfunction in cultured human liver HepG2 cells. A pathway‐focused gene expression analysis resulted in marked up‐regulation of three genes CCL21, CCNC and UGT1A4 as well as the down‐regulation of three genes CSF2, CYP7A1 and CYP2E1 in the usnic acid‐treated cells compared with the vehicle controls. This study demonstrated the toxicity of usnic acid in human liver HepG2 cells suggesting an oxidative mechanism of action.