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

Abstract

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.)

Drug–Induced Liver Injury: Mechanisms and Test Systems

“…16 Monocrotaline administration produces a VOD-like lesion in rats. 17 In this experimental model, damage to SECs precedes evidence of parenchymal cell toxicity and appears to relate to SEC glutathione. Depletion of glutathione sensitizes animals to monocrotaline, and constant infusion of glutathione or N-acetylcysteine during monocrotaline administration prevents the injury.…”

Cordyceps sinensis protects against liver and heart injuries in a rat model of chronic kidney disease: a metabolomic analysis

“…Previously reported work demonstrated that hepatic glutathione was significantly decreased in alcoholic liver disease [44] , hepatic veno-occlusive disease [45] , chronic hepatitis C [46] , Wilson's disease [47] and other liver-related diseases. The significant depletion of hepatic glutathione in the OP rats was a marker of the disruption of cellular redox status related to CKD-induced liver injury.…”

The effect of modulation of glutathione cellular content on busulphan-induced cytotoxicity on hematopoietic cells in vitro and in vivo

“…Animals treated with N-acetyl-L-cysteine were protected against monocrotaline-induced hepatic VOD as shown by less histological changes and clinical manifestation. 23 The cellular content of GSH may be modulated in vitro and in vivo by different treatments. 24 Precursors of GSH, such as methionine or N-acetyl-L-cysteine (NAC), increase the cellular content of GSH.…”