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.
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| Creator |
Roy, Dijendra Nath
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| Subject |
Cell Biology & Physiology
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| 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
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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
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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.
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| Date |
2010
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| 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. |
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| Relation |
http://www.eprints.iicb.res.in/413/
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