Protection of acetaminophen induced mitochondrial dysfunctions and hepatic necrosis via Akt-NF-kappaB pathway: role of a novel plant protein.
Oxidative stress is a major cause of drug induced hepatic diseases. The present study aims to investigate the antioxidative signaling mechanism of a protein isolated from the herb, Cajanus indicus against acetaminophen induced necrotic cell death. We found that incubation of hepatocytes with the protein prevented acetaminophen-induced loss in cell viability, reduction in glutathione level and enhancement of reactive oxygen species generation. Treatment of mice with the protein before administration of acetaminophen also reduced serum nitrite and TNF-alpha formation. Moreover, it counteracted acetaminophen-induced loss in mitochondrial membrane potential, loss in adenosine tri phosphate and rise in intracellular calcium. Investigating the cell signaling pathways, we found that the protein exerts its protective action via the activation of NF-kappaB and Akt and deactivation of STAT-1. Surprisingly, no role of ERK1/2 or STAT-3 was found in the protein-mediated protection of hepatocytes during acetaminophen exposure. Finally, we found that acetaminophen introduces necrosis as the primary phenomena of cell death and protein treatment decreased the necrotic process as evident from the DNA fragmentation and flow-cytometry studies. In addition, administration of the protein to mice before acetaminophen application showed fewer number of TUNEL positive cells. Combining, data suggest that the protein possesses cytoprotective activity against acetaminophen-induced oxidative cellular damage and prevents hepatocytes from necrotic death.
Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, West Bengal, India.
Ayantika
A
Ghosh
Parames C
PC
Sil
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D036561:Cajanus / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010940:Plant Proteins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D016328:NF-kappa B; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione