14-Deoxyandrographolide targets adenylate cyclase and prevents ethanol-induced liver injury through constitutive NOS dependent reduced redox signaling in rats

• Published in: Food and chemical toxicology 2013-09, Vol.59, p.236-248
• Main Authors: Mandal, Samir, Nelson, Vinod K., Mukhopadhyay, Sibabrata, Bandhopadhyay, Sukdeb, Maganti, Lakshmi, Ghoshal, Nanda, Sen, Gargi, Biswas, Tuli
• Format: Article
• Language: English
• Subjects: 14-Deoxyandrographolide; Addictive behaviors; Adenylate cyclase; Adenylyl Cyclases - chemistry; Adenylyl Cyclases - metabolism; Adult and adolescent clinical studies; alcohol abuse; Alcoholism; Alcoholism and acute alcohol poisoning; Andrographis - chemistry; Animals; Antioxidants - isolation & purification; Antioxidants - pharmacology; Antioxidants - therapeutic use; apoptosis; Apoptosis - drug effects; Biological and medical sciences; calmodulin; Cells, Cultured; Chronic alcoholism; Constitutive nitric oxide synthase; cyclic AMP; Cyclic AMP - agonists; Cyclic AMP - metabolism; Diterpenes - isolation & purification; Diterpenes - pharmacology; Diterpenes - therapeutic use; enzyme activity; ethanol; Female; glutamate-cysteine ligase; Glutamate-Cysteine Ligase - chemistry; Glutamate-Cysteine Ligase - metabolism; Hep G2 Cells; hepatocytes; Hepatotoxicity; Humans; liver; Liver - cytology; Liver - drug effects; Liver - metabolism; Liver - pathology; liver diseases; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Liver Diseases, Alcoholic - prevention & control; Medical sciences; nitric oxide; Nitric Oxide - agonists; Nitric Oxide - metabolism; nitric oxide synthase; Nitric Oxide Synthase Type III - chemistry; Nitric Oxide Synthase Type III - metabolism; Oxidation-Reduction; oxidative stress; Oxidative Stress - drug effects; Plant Leaves - chemistry; protective effect; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Second Messenger Systems - drug effects; Toxicology; γ-Glutamylcysteine synthetase
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.05.056

•14-Deoxy andrographolide prevents ethanol-induced liver injury.•Preventive effect involves up-regulation of γ-glutamylcysteine synthetase.•γ-Glutamylcysteine synthetase up-regulation depends on constitutive NOS activation.•Constitutive NOS is activated through improved adenylyl cyclase-cAMP signaling. Chronic alcoholism is one of the most common causes of liver diseases worldwide. Nitric oxide (NO) has been proposed to have potential for clinical application against chronic hepatocellular injuries. However, mechanisms underlying hepatoprotective functions of NO in ethanol-induced apoptosis are largely unknown. Sprauge–Dawley rats were exposed to ethanol for 8weeks. Half of the ethanol-fed animals received 14-deoxyandrographolide (14-DAG) treatment for the last 4weeks of study. Preventive effect of 14-DAG against ethanol-induced hepatotoxicity involved constitutive nitric oxide synthase (cNOS) activation followed by up-regulation of γ-glutamylcysteine synthetase activity and reduced oxidative stress. Enhanced interaction of cNOS with caveolin-1 caused down-regulation of enzyme activity and led to depletion of NO in the hepatocytes of ethanol-fed animals. 14-DAG acted as activator of adenylate cyclase and modulated cyclic AMP (cAMP) mediated expression of caveolin-1 and calmodulin. This eventually favored activation of cNOS through inhibition of cNOS-caveolin-1 interaction. Our results suggest that, protective effect of 14-DAG against ethanol-induced hepatic injury is based on its ability to reduce oxidative stress through cNOS dependent improvement of redox status. 14-DAG mediated activation of adenylate cyclase-cAMP signaling leading to up-regulation of cNOS may provide a promising approach in the prevention of liver diseases during chronic alcoholism.