Relationship Between Glutathione Concentration and Metabolism of the Pyrrolizidine Alkaloid, Monocrotaline, in the Isolated, Perfused Liver

Yan, Chong Chao; Huxtable, Ryan J.

doi:10.1006/taap.1995.1017

Cited by 56 publications

(31 citation statements)

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“…Synthetic dehydromonocrotaline reproduces the toxicity of MCT. 27,28 In an isolated liver, dehydromonocrotaline readily conjugates with GSH to form the less toxic secondary metabolite GSDHP, 22 which is excreted in high concentrations into the bile. MCT (0.5 mM) also induces a 30-fold increase in the biliary excretion of GSH in an isolated, perfused liver, which depletes hepatic GSH stores.…”

Section: Discussionmentioning

confidence: 99%

“…17,20 The amount of dehydromonocrotaline available for these presumably intoxicating pathways is affected markedly by the GSH content of the liver. 22 GSH conjugates with dehydromonocrotaline to form glutathione dehydropyrrolizidine (GSDHP), a compound of much lower toxicity that is released in high concentration into the bile. 20 Sulfur amino acids, such as methionine and cysteine, that elevate hepatic GSH content also protect against PA toxicity.…”

Section: Introductionmentioning

confidence: 99%

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The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

Amin

Hassan²,

Awad³

et al. 2011

IJN

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Objective The objective of the present study was to determine the ability of cerium oxide (CeO 2 ) nanoparticles to protect against monocrotaline (MCT)-induced hepatotoxicity in a rat model. Method Twenty male Sprague Dawley rats were arbitrarily assigned to four groups: control (received saline), CeO 2 (given 0.0001 nmol/kg intraperitoneally [IP]), MCT (given 10 mg/kg body weight IP as a single dose), and MCT + CeO 2 (received CeO 2 both before and after MCT). Electron microscopic imaging of the rat livers was carried out, and hepatic total glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) enzymatic activities were quantified. Results Results showed a significant MCT-induced decrease in total hepatic GSH, GPX, GR, and GST normalized to control values with concurrent CeO 2 administration. In addition, MCT produced significant increases in hepatic CAT and SOD activities, which also ameliorated with CeO 2 . Conclusions These results indicate that CeO 2 acts as a putative novel and effective hepatoprotective agent against MCT-induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

Amin

Hassan²,

Awad³

et al. 2011

IJN

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“…It is a pyrrolizidine alkaloid that is metabolically activated by hepatic P-450s to the toxic, alkylating pyrrole, dehydromonocrotaline (see review 5 ). This reactive metabolite is detoxified by glutathione conjugation 3,6,7 The current study examines whether intraportal infusion of GSH can prevent HVOD in vivo and addresses the mechanism of protection.…”

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confidence: 99%

Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat

2000

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Depletion of sinusoidal endothelial cell glutathione (GSH) has been proposed as a common mechanism leading to hepatic veno-occlusive disease (HVOD). This study examines whether intraportal infusion of GSH can prevent HVOD in the monocrotaline rat model. HVOD was induced in rats with monocrotaline 160 mg/kg i.g. on day 0. GSH was infused intraportally by mini-osmotic pump. Monocrotaline decreased GSH in sinusoidal endothelial cells, but not in liver homogenate. Infusion of GSH, 2 mol/hr starting day Ϫ 1, prevented the decrease in sinusoidal endothelial cell GSH and protected against histological and clinical evidence of HVOD. Protection by GSH was dose-dependent (0.5-2 mol/hr). In rats receiving continuous GSH infusion, treatment with buthionine sulfoximine starting day Ϫ 2 decreased sinusoidal endothelial cell GSH and attenuated the protective effect of GSH against monocrotaline. GSH infusion starting 24 hours after monocrotaline (''glutathione rescue'') offered substantial protection to most rats. N-acetyl-Lcysteine conferred protection, but N-acetyl-D-cysteine (an antioxidant that is not a precursor for GSH) had little or no protective effect, and 4-hydroxy TEMPO, a free radical scavenger, was not protective. Discontinuation of the GSH infusion 5 days after monocrotaline administration led to severe hepatic venoocclusive disease on day 6. In conclusion, monocrotaline selectively depletes sinusoidal endothelial cell GSH. Intraportal infusion of GSH protects against monocrotaline toxicity, at least partially by maintaining sinusoidal endothelial cell GSH levels. Glutathione infusion started after monocrotaline is partially protective. Monocrotaline induces prolonged changes in the liver that remain suppressed as long as GSH is infused. (HEPATOLOGY 2000;31:428-434.)

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“…The importance of intracellular glutathione on toxin elimination of PAs has been shown in numerous studies. 3,18,56 In addition, qualitative and quantitative species differences in the liver capacity of glucuronidation are said to be responsible for insensitivity to senecio-alkaloids of some animal species. 16 A further type of hepatic lipidosis associated with encephalopathy, named ''white liver disease,'' has been described concurrently with cobalt deficiency in sheep 22,24 and goats, 21 causing a decreased activity of the vitamin B12-dependent enzymes methyl-malonyl-CoA mutase 23 and methionine synthase 22 and a consequent accumulation of branched-chain fatty acids (BCFAs) in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Lipodystrophy in Galloway Calves

et al. 2017

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Hepatic lipodystrophy in Galloway calves is a fatal liver disease affecting a small proportion of the Galloway breed described in different parts of Europe and North America during the past decades. The clinical findings include a diversity of neurological signs. Clinical pathology findings frequently indicate hepatobiliary disease. Postmortem examination reveals an enlarged, pale yellow, and firm liver. Histologic lesions include hepatic fibrosis, hepatic lipidosis, and bile duct hyperplasia. To date, the etiopathogenesis remains obscure. Infectious causes, intoxications, and a hereditary origin have been considered. We describe hepatic lipodystrophy in Galloway calves from an extensively farmed cow-calf operation in southern Germany. Main clinical findings in 6 calves were consistent with hepatic encephalopathy. Clinical pathology findings in 5 of 6 tested animals revealed increased concentration of total bilirubin (maximum value [MV], 54 mmol/l; reference range [RR], <8

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Relationship Between Glutathione Concentration and Metabolism of the Pyrrolizidine Alkaloid, Monocrotaline, in the Isolated, Perfused Liver

Cited by 56 publications

References 0 publications

The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat

Hepatic Lipodystrophy in Galloway Calves

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