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Protective Effect of Andrographolide against Copper Mediated Hepatological Disorders in Rats.

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Protective Effect of Andrographolide against Copper Mediated Hepatological Disorders in Rats.
Creator Roy, Dijendra Nath
Subject Cell Biology & Physiology
Description Copper toxicosis with hepatic copper accumulation is associated with chronic cholestasis which eventually leads to cirrhosis of the liver. Liver is considered to be the main site for copper homeostasis in the body, and excess of this transition metal induces apoptotic changes in the hepatocytes followed by cirrhosis which eventually culminates in liver failure. We were interested to find out the underlying mechanism leading to the development of copper toxicity and to find out a short term treatment strategy against it. For this purpose, we have developed an animal model with rats. In the first chapter, we have established the fundamental mechanism of copper toxicity developed in liver of young rats. Chronic exposure to copper induces hepatocellular apoptosis with greater injury in the periportal region compared to the perivenous region. Here we have identified the factors responsible for the development of regional damage in the liver under in vivo conditions. Enhanced production of reactive oxygen species with predominance of superoxide radical indicates the contribution of redox imbalance in the process. This may be linked with copper catalyzed oxidation of reduced glutathione to oxidized glutathione resulting in the generation of superoxide radical. Downregulation of copper-zinc superoxide dismutase in consequence of the degradation of this enzyme, causes decreased dismutation of superoxide radical that further contributes to the enhanced level of superoxide radical in the periportal region. Decreased functioning of manganese superoxide dismutase activity, reduction in mitochondrial thiol/disulphide ratio and generation of superoxide radical were much higher in the mitochondria from periportal region, which point to the involvement of this 2 organelle in the regional hepatotoxicity observed during copper exposure. This was supported by copper-mediated enhanced mitochondrial dysfunction as evident from adenosine triphosphate depletion, collapse of mitochondrial membrane potential and induction of mitochondrial permeability transition. Results suggest the active participation of superoxide radical in inducing mitochondrial dysfunction preferentially in the periportal region that eventually leads to the development of hepatotoxicity due to copper exposure under in vivo condition. In the second chapter, we have ascertained a treatment schedule with andrographolide and D-penicillamine used in combination manner, which gives a promising result against copper induced liver damage in rats. Copper toxicity results from the cytoplasmic copper accumulation in periportal zone of liver due to intracanalicular cholestasis. We have shown that chronic exposure to copper caused oxidative stress and induced hepatocellular apoptosis in rats leading to periportal fibrosis. Despite several studies on the treatment of copper toxicosis, the result of these experimental therapies to date remains unsatisfactory. D-penicillamine, a metal chelator, still represents the drug of choice for the treatment of copper toxicosis. Long treatment regime and side effects after prolonged use remains a major hindrance to successful treatment with D-penicillamine. Effective short term treatment strategies involve coadministration of this agent with another hepatoprotective drug, andrographolide which is our drug of choice. Andrographolide exerts choleretic and anticholestatic effects and reverts back the cholestasis efficiently. Andrographolide potentiates the cytoprotective effect of D-penicillamine by accentuating the simultaneous removal of copper through bile and urine respectively. So, co-administration of andrographolide with D-penicillamine reduces hepatocyte death. This is accompanied by inhibition of mitochondrial depolarization, cytochrome c release, and activation of caspase cascade. Toxic events 3 are consequense of oxidative stress and generation of proinflmmatory cytokines, we suggest that the antiapoptotic activity of combination therapy with andrographolide and D-penicillamine can be related to their ability to prevent the liver damage associated with copper toxicosis. To conclude, simultaneous treatment with andrographolide and Dpenicillamine synergistically exert antifibrotic effect and may therefore have a therapeutic implication for reducing copper overload as well as hepatic fibrosis associated with copper toxicosis. A change in the feeding pattern among Indian children is the first option to prevent the development Indian Childhood Cirrhosis. There should be a greater awareness among pediatricians about this disease to enable early diagnosis. Most of the patients are diagnosed at a very late stage of this disease and as a result commonly leads to death. We hope that, the research findings of our study will have a good implication in human society and can be used successfully for the treatment of human population, suffering from copper toxicity in future.
Date 2010
Type Thesis
Format application/pdf
Identifier http://www.eprints.iicb.res.in/413/1/DIJEN_2010.pdf
Roy, Dijendra Nath (2010) Protective Effect of Andrographolide against Copper Mediated Hepatological Disorders in Rats. PhD thesis, Jadavpur University.
Relation http://www.eprints.iicb.res.in/413/