Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents

Landon, Erwin J.; Naukam, Rebecca; Sastry, B. V. Rama

doi:10.1016/0006-2952(86)90369-2

Cited by 101 publications

(44 citation statements)

References 25 publications

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“…However, the borderline between the two types of toxic cell death (necrosis and apoptosis) remains unclear. Landon et al [22] have extended the observations on the relationship between necrosis and Ca 2+ concentration by showing that several calcium blocking agentsnifedipine, nitrendipine, CPZ and VR-prevent Ca 2+ accumulation and hepatic necrosis produced by experimental hepatotoxins including acetaminophen, carbon tetrachloride, chloroform, dimethylnitrosamine and thioacetamide. Some of these hepatotoxins also induce apoptosis [20,23,30,33,35].…”

Section: Discussionmentioning

confidence: 91%

“…As mentioned in the Introduction, this concept, called "the calcium hypothesis", that a loss of regulation of intracellular Ca 2+ concentration constitutes the final common pathway leading to cell death is supported by recent reports in which other chemicals have been used [28,32,34,40]. In addition, the cell death caused by those chemicals is known to be ameliorated by treatment with Ca 2+ -channel blockers and Ca 2+ -calmodulin antagonists [3,16,22,26].…”

Section: Discussionmentioning

confidence: 98%

“…These findings suggest that the two types of toxic cell death, apoptosis and necrosis, might be induced by different processes, the first being a Ca 2+ dependent pathway and the second a Ca 2+ -independent pathway. The mechanism by which VR, a well known Ca 2+ channel blocker, protects hepatocytic death is under some question, as are other Ca 2+ -channel blockers, nifedipine and nitrendipine [22]. The hepatocyte is not thought to be an excitable cell type and no voltage sensitive Ca 2+ channels have yet been detected.…”

Section: Discussionmentioning

confidence: 99%

“…The concept that a loss of Ca 2+ regulation is the final common pathway leading to cell death is supported by several recent observations [28,32,34,40]. The most compelling argument for the calcium hypothesis is that Ca 2+ -channel blockers and Ca 2+ -calmodulin antagonists can ameliorate the toxic death of hepatocytes in vivo and in vitro caused by clinically important hepatotoxic chemicals [16,22,26], including D-Galactosamine (GalN) [3]. Similarly, it has been shown that a sustained rise in [Ca 2+ ]i is associated with the DNA fragmentation that is characteristic of apoptosis, or programmed cell death, in thymocytes [24,25].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Ethanol administration in vivo increases the calcium content in the liver of rats and mice, and this effect was enhanced by glutathione depletion or co-administration of iron, suggesting a synergism between ethanol and these agents (19,20). The rise in liver cell calcium content may contribute to the cell injury process associated with toxic agents, or it may be a relatively late consequence of cell injury (21).…”

mentioning

confidence: 99%

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Andrés

Cederbaum

2002

Journal of Biological Chemistry

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The objective of this work was to investigate whether CYP2E1-and oxidative stress-dependent toxicity in HepG2 cells is mediated by an increase of cytosolic Ca in the toxicity. Reactive oxygen production was similar in media with or without calcium, indicating that calcium was not modulating CYP2E1-dependent oxidative stress. Toxicity, lipid peroxidation, and the increase of Ca 2؉ in E47 cells exposed to iron-AA were inhibited by ␣-tocopherol. E47 cells (but not C34 cells) exposed to iron-AA showed increased calpain activity in situ (40-fold). The toxicity in E47 cells mirrorred calpain activation and was inhibited by calpeptin, suggesting that calpain activation plays a causal role in toxicity. These results suggest that CYP2E1-dependent toxicity in this model depends on the activation of lipid peroxidation, followed by an increased influx of extracellular Ca 2؉

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Isoenzymes of carbohydrate metabolism in primary cultures of hepatocytes from thioacetamide-induced rat liver necrosis: Responses to growth factors

Cascales¹,

Martı́n-Sanz²,

Álvarez

et al. 1992

Hepatology

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Hepatocytes isolated from the liver of rats after a necrotizing dose of thioacetamide (6.6 mmol/kg) were used to study the postnecrotic process of liver regeneration. Flow cytometry analysis revealed populations of dedifferentiated hepatocytes exhibiting physical properties (size and fluorescence emission at 530 nm) similar to those found in fetal (22 days old) liver cells. The percentage of these cells increased progressively from 24 to 48 and 72 hr after thioacetamide administration. In primary cultures of hepatocytes the effects of phorbol 12-myristate 13-acetate, bombesin and insulin were investigated on the 6-phosphofructo 2-kinase/fructose 2,6 bisphosphate system. Bombesin and insulin stimulated 6-phosphofructo 2-kinase activity and fructose 2,6-bisphosphate content both in control and in thioacetamide-treated hepatocytes. However, phorbol 12-myristate 13-acetate stimulated 6-phosphofructo 2-kinase activity and increased fructose 2,6-bisphosphate concentration in thioacetamide-treated liver cells, whereas no similar response was found in hepatocytes from control rats. The response of postnecrotic thioacetamide-treated hepatocytes to phorbol 12-myristate 13-acetate was similar to that obtained from 22-day-old fetal liver cells, which reveals that different methods might control fructose 2,6-bisphosphate content and therefore the mechanisms of glycolysis and gluconeogenesis at this regulatory step. The lack of response to glucagon of glycogen phosphorylase a and 6-phosphofructo 2-kinase from thioacetamide-treated hepatocytes may indicate that the expression of specific enzymes of carbohydrate metabolism undergoes transitions to less-differentiated isoenzymatic forms. Moreover, the isoenzyme pattern of hexokinases elicits a complete disturbance in glucokinase and hexokinases activities.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents

Cited by 101 publications

References 25 publications

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.

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.

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Isoenzymes of carbohydrate metabolism in primary cultures of hepatocytes from thioacetamide-induced rat liver necrosis: Responses to growth factors

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