Negundoside, an irridiod glycoside from leaves of Vitex negundo, protects human liver cells against calcium-mediated toxicity induced by carbon tetrachloride

• Published in: World journal of gastroenterology : WJG Vol. 14; no. 23; pp. 3693 - 3709
• Main Authors: Tasduq, Sheikh A, Kaiser, Peerzada J, Gupta, Bishan D, Gupta, Vijay K, Johri, Rakesh K
• Format: Journal Article
• Language: English
• Published: United States Indian Institute of Integrative Medicine, CSIR, Jammu-Tawi-180001, Jammu and Kashmir, India 21.06.2008
• Subjects: Antioxidants - isolation & purification; Antioxidants - pharmacology; Apoptosis - drug effects; Calcium - metabolism; Carbon Tetrachloride - toxicity; Caspase 3 - metabolism; Caspase Inhibitors; Cell Line, Tumor; Cell Survival - drug effects; Cyclic AMP - metabolism; Cytochrome P-450 CYP2E1 - metabolism; Cytochromes c - metabolism; Cytoprotection; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Glutathione - metabolism; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Iridoid Glycosides; Iridoids - isolation & purification; Iridoids - pharmacology; Lipid Peroxidation - drug effects; Membrane Potential, Mitochondrial - drug effects; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Oxidative Stress - drug effects; Phospholipases A2, Cytosolic - antagonists & inhibitors; Phospholipases A2, Cytosolic - metabolism; Plant Leaves; Reactive Oxygen Species - metabolism; Silymarin - pharmacology; Vitex - chemistry; 四氯化碳; 氧化应力; 肝细胞; Oxidative stress; Silymarin; Calcium; Negundoside; Toxicity; Carbon tetrachloride; HuH-7; CYP 2E1
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.14.3693

AIM： To evaluate the protective effect of 2′-p-hydroxy benzoylmussaenosidic acid [negundoside （NG）, against carbon tetrachloride （CCl4）-induced toxicity in HUH-7 cel Is. METHODS： CCI4 is a well characterized hepatotoxin, and inducer of cytochrome P450 2E1 （CYP2E1）-mediated oxidative stress. In addition, lipid peroxidation and accumulation of intracellular calcium are important steps in the pathway involved in CCl4 toxicity. Liver cells （HUH-7） were treated with CCI4, and the mechanism of the cytoprotective effect of NG was assessed. Silymarin, a known hepatoprotective drug, was used as control. RESULTS： NG protected HUH-7 cells against CCl4 toxicity and loss of viability without modulating CYP2E1 activity. Prevention of CCl4 toxicity was associated with a reduction in oxidative damage as reflected by decreased generation of reactive oxygen species （ROS）, a decrease in lipid peroxidation and accumulation of intracellular Ca^2＋ levels and maintenance of intracellular glutathione homeostasis. Decreased mitochondrial membrane potential （MMP）, induction of caspases mediated DNA fragmentation and cell cycle arrest, as a result of CCl4 treatment, were also blocked by NG. The protection afforded by NG seemed to be mediated by activation of cyclic adenosine monophosphate （cAMP） synthesis and inhibition of phospholipases （cPLA2）. CONCLUSION： NG exerts a protective effect on CYP2E1-dependent CCl4 toxicity via inhibition of lipid peroxidation, followed by an improved intracellular calcium homeostasis and inhibition of Ca^2＋-dependent proteases.