Combination therapy with andrographolide and D-penicillamine enhanced therapeutic advantage over monotherapy with D-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis
Long treatment regime with D-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term D-penicillamine treatment is associated with numerous side effects. The limitations of D-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of D-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of D-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. D-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to D-penicillamine regime appeared to increase protection of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNF{alpha} production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis.
- OSTI ID:
- 21535203
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 250, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.09.027; PII: S0041-008X(10)00378-9; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ALANINES
AMINOTRANSFERASES
APOPTOSIS
COPPER
EXCRETION
FIBROSIS
INHIBITION
LIVER
LIVER CELLS
MITOCHONDRIA
NECROSIS
PENICILLAMINE
RATS
RECEPTORS
RETICULOENDOTHELIAL SYSTEM
SAFETY
THERAPY
AMINO ACIDS
ANIMAL CELLS
ANIMAL TISSUES
ANIMALS
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHELATING AGENTS
CLEARANCE
DIGESTIVE SYSTEM
DRUGS
ELEMENTS
ENZYMES
GLANDS
MAMMALS
MEDICINE
MEMBRANE PROTEINS
METALS
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
SOMATIC CELLS
THIOLS
TRANSFERASES
TRANSITION ELEMENTS
VERTEBRATES