Galactosamine-induced apoptosis in the primary mouse hepatocyte cultures

Tsutsui, Shigeki; Hirasawa, Kensuke; Takeda, Makio; Itagaki, Shin Ichi; Kawamura, Seiji; Maeda, Ken; Mikami, Takeshi; Doi, Kunio

doi:10.1016/s0940-2993(97)80044-9

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…In addition, it has been also reported that agents such as dimethylnitrosamine, 1,1-dichloroethylene, heliotrine and thioacetamide can induce both apoptosis and necrosis of hepatocytes in vivo [6,8,9,18,21]. In the previous study, we reported that GalN also could induce apoptotic death in the cultured hepatocytes from C57BL/6N mice, followed by necrotic death [27].…”

Section: Discussionmentioning

confidence: 73%

“…At this point, activities of sGOT and sGPT reached the maximum level. Our previous examinations with cultured mouse hepatocytes exposed to GalN revealed that the typical ultrastructural feature of necrosis was observed when the intracellular enzyme leaked to medium [27]. Differentiation between chemically induced apoptosis and necrosis is considerably difficult, but, as Corcoran et al [2] stated, morphology at the cell and ultrastructural levels remains the golden standard for the differentiation between apoptosis and necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…From the results of some preliminary examinations of GalN-intoxication in mice, we had a strong impression that at least a part of such acidophilic single cell necrosis of hepatocytes might be apoptosis. As the first step to confirm this point, we carried out the examination of in vitro hepatotoxicity of GalN and clarified that GalN could induce apoptotic death of hepatocyte at least in vitro [27].…”

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confidence: 90%

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Apoptosis of Murine Hepatocytes Induced by High Doses of Galactosamine.

Tsutsui

Hirasawa

Takeda

et al. 1997

The Journal of Veterinary Medical Science

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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.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

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Apoptosis of Murine Hepatocytes Induced by High Doses of Galactosamine.

Tsutsui

Hirasawa

Takeda

et al. 1997

The Journal of Veterinary Medical Science

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“…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].…”

Section: Introductionmentioning

confidence: 73%

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.

et al. 2003

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Studies were conducted in C57BL/6N Crj male mice and in cultured hepatocytes to clarify the relationship between galactosamine (GalN) induced apoptosis and [Ca 2+ ]i kinetics. Chlorpromazine (CPZ), a Ca 2+ -calmodulin antagonist, and verapamil (VR), a Ca 2+ -channel blocker each inhibited GalN-induced DNA fragmentation and the appearance of apoptotic bodies. The kinetics of calcium uptake were evaluated using a calcium analyzer with the acetoxymethyl ester of fura-PE3 (fura-PE3/AM, 2.5 µM) as the calcium reporter. An increase in [Ca 2+ ]i was detected in the cultured hepatocytes within 3 hours after treatment with 20 mM GalN; this increase was inhibited by pretreatment with either 20 µM CPZ or 30 µM VR. Ca 2+ imaging by confocal laser scanning microscopy showed that increase in [Ca 2+ ]i after treatment with GalN was initially localized around nuclei, while [Ca 2+ ]i signals were later diffuse and observed throughout the cytoplasm. The activities of lactate dehydrogenase (LDH) and serum glutamate-pyruvate transaminase (sGPT), used as indicators of plasma membrane damage and leakage, however, were not reduced by pretreatment with CPZ or VR. From these findings, we infer that the DNA fragmentation in GalN-induced hepatocyte apoptosis is associated with an elevation in the perinuclear concentration of Ca 2+ , but GalN-induced necrotic cell death is triggered through pathway(s) that are insensitive to blockage of Ca 2+ influx and therefore appear to occur independently of elevation in [Ca 2+ ]i. These results help to clarify the role of calcium flux in hepatocyte apoptosis and necrosis induced by exposure to hepatotoxins in vivo and in vitro.

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“…Recent studies have demonstrated that apoptosis also contributes to galactosamineinduced liver injury by increasing TNF-␣ production * To whom correspondence should be addressed at present address: School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan E-mail: takenaka@isc.meiji.ac.jp Abbreviations: AGPC, acid guanidium thiocyanate-phenolchloroform; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HPLC, high-performance liquid chromatography; LDH, lactate dehydrogenase; PL, phospholipids; TG, triglyceride; ␣-TTP, ␣-tocopherol transfer protein; TC, total cholesterol. (13)(14)(15).…”

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confidence: 99%

Galactosamine-Induced Acute Liver Injury in Rats Reduces Hepatic .ALPHA.-Tocopherol Transfer Protein Production

Takenaka

Kita

Ikeya

et al. 2007

J Nutr Sci Vitaminol

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SummaryThe liver plays the main role in the secretion of food-derived ␣ -tocopherol into the circulation through the functioning of ␣ -tocopherol transfer protein ( ␣ -TTP). However, the effect of liver disease on ␣ -TTP level and ␣ -tocopherol metabolism has not been clarified. We examined the amount of liver ␣ -TTP and its effect on serum ␣ -tocopherol concentration in liver injury. Male Wistar rats were injected intraperitoneally with D -galactosamine at 800 mg/kg body weight, and liver and serum lipid concentrations, ␣ -tocopherol concentrations, and hepatic ␣ -TTP mRNA and protein levels were measured at 24, 48, and 72 h after injection. On the basis of body weight changes and serum transaminase activities, the livers were found to be in an injured state 24 and 48 h after galactosamine injection but had recovered by 72 h. The hepatic ␣ -TTP mRNA level was reduced throughout the experimental period, and at 48 h after injection the ␣ -TTP protein level had begun to decrease. Lipid and ␣ -tocopherol concentrations in the serum were decreased at 24 and 48 h after injection and increased at 72 h. Liver lipid concentrations were increased at 24 and 48 h after injection, but the liver ␣ -tocopherol concentration was unchanged. These results show that galactosamine-induced liver injury decreases hepatic ␣ -TTP synthesis in rats. Serum ␣ -tocopherol concentration was not directly affected by the acute change in hepatic ␣ -TTP level, suggesting that the chronic changes in ␣ -TTP activity would be necessary to regulate serum ␣ -tocopherol concentration.

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Galactosamine-induced apoptosis in the primary mouse hepatocyte cultures

Cited by 14 publications

References 22 publications

Apoptosis of Murine Hepatocytes Induced by High Doses of Galactosamine.

Apoptosis of Murine Hepatocytes Induced by High Doses of Galactosamine.

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.

Galactosamine-Induced Acute Liver Injury in Rats Reduces Hepatic .ALPHA.-Tocopherol Transfer Protein Production

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