Apoptosis of Murine Hepatocytes Induced by High Doses of Galactosamine.

Abstract

ABSTRACT. Apoptosis induced by high doses of Galactosamine (GalN) was investigated in mice hepatocytes in vivo. In mice intraperitoneally (ip) treated with GalN 3 g/kg, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells were first observed at 6 hr postadministration (PA). Both acidophilic bodies in hematoxylin and eosin (HE)-stained sections and TUNEL-positive cells were markedly found at 24 hr PA. At 48 hr PA, cellular degeneration and necrosis of hepatocytes were prominently observed, and TUNEL-positive cells were scarcely found. In the mice ip treated with GalN 1.5 g/kg, the lesion was milder than that in those treated with GalN 3 g/kg. Acidophilic bodies and TUNEL-positive cells were scarcely found at 24 hr PA, whereas they were markedly seen at 48 hr PA. In addition, a ladder-like DNA fragmentation pattern by agarose gel electrophoresis was observed most remarkably at 24 hr PA with GalN 3 g/kg and at 48 hr PA with GalN 1.5 g/kg, and less distinctly at 48 hr PA with GalN 3 g/kg. On the other hand, sGOT and sGPT activities increased prominently at 48 hr PA with GalN 3 g/kg. These results suggest that the cell death induced by high dose of GalN may be caused by apoptosis, and subsequently by necrosis in vivo. -KEY WORDS: apoptosis, galactosamine, hepatotoxicity, liver, mouse.

D-Galactosamine Induced Hepatocyte Apoptosis is Inhibited in vivo and in Cell Culture by a Calcium Calmodulin Antagonist, Chlorpromazine, and a Calcium Channel Blocker, Verapamil.

“…In previous work in vitro [42] and in vivo [41], we have demonstrated that GalN first induces apoptotic death of hepatocytes in C57BL/6N mice, followed temporally by necrosis. The toxicity of GalN results from a dose dependent depletion of uridine nucleotides, which causes inhibition of RNA synthesis and disturbance in the biosynthesis of glycoproteins [4] leading to deterioration of cell membranes and associated increases in the intracellular concentration of calcium ions [5,6].…”

Aggravation of Galactosamine Hepatotoxicity by Albumin in Rats

“…This in turn inhibits mRNA and protein syntheses, alters the composition of cellular membranes, and finally leads to cellular damage as a result of lipid peroxidation [18][19][20][21] . The hepatocyte death is represented as apoptosis and subsequently necrosis 22 in vivo 3,6,8,23 and in vitro 24 . Other mechanisms of the hepatotoxicity have been explained as follows.…”

“…As a hepatotoxicant, in the present study, we chose D-(+)-galactosamine hydrochloride (GalN), which has been used to induce hepatic lesions in animals as a human hepatitis model [2][3][4] . In the animal model, the following have been reported: increases in the blood levels of tumor necrosis factor-α (TNF-α), interleukin-1, and interferon-γ 5 ; and occurrence of apoptosis and necrosis of hepatocytes [6][7][8] , as well as infiltration of polymorphonuclear cells (PMNs) and macrophages 9 . Moreover, the contribution of T lymphocytes and the reticulo-endothelial system to lesion development has also been reported 5,10 .…”

Hepatoprotective Effects of a Concentrate and Components of Sake against Galactosamine (GalN)-Induced Liver Injury in Mice

“…21,22) Under the conditions used in this study, GalN-induced hepatic DNA fragmentation was observed by the TUNEL method (data not shown). Hepatic DNA fragmentation quantified by the ELISA method in the GalN group was 2.0-fold higher than that in the control group (data not shown).…”

“…Liver injury was induced by an intraperitoneal injection of 1500 mg/kg BW GalN (150 mg/ml of GalN, 10 ml/kg BW) as previously described. 21,22) Untreated mice were injected with saline. The mice were killed by decapitation to obtain blood and liver 24 hr after the injection.…”