DeLeve L D, Wang X, Kuhlenkamp J F, Kaplowitz N
Center for Liver Diseases and the Division of Gastrointestinal and Liver Diseases, USC School of Medicine, Los Angeles, CA 90033, USA.
Hepatology. 1996 Mar;23(3):589-99. doi: 10.1002/hep.510230326.
The mechanisms leading to hepatic venoocclusive disease (HVOD) remain largely unknown. Azathioprine and monocrotaline were studied as part of a series of studies looking at a variety of toxins that induce HVOD to find common features that might be of pathogenic significance. In a previous study, dacarbazine showed selective in vitro toxicity to sinusoidal endothelial cells (SEC) compared with hepatocytes and a key role for SEC glutathione (GSH) was demonstrated. Murine SEC and hepatocytes were isolated and studied in culture. Azathioprine and monocrotaline were found to be selectively more toxic to SEC than to hepatocytes. The relative resistance of hepatocytes to azathioprine was due to enhanced GSH defense: hepatocytes exposed to azathioprine maintained intracellular GSH levels better than SEC, particularly when supplemental GSH precursors were added, and hepatocyte resistance was completely overcome by depletion of intracellular GSH. In contrast, monocrotaline toxicity in hepatocytes was largely unaffected by depletion of GSH, which suggests that selectivity of monocrotaline for SEC may be attributable to differences in metabolic activation. Both compounds are detoxified by GSH in SEC, as demonstrated by enhanced toxicity in the presence of buthionine sulfoximine (BSO) and attenuation of toxicity with exogenous GSH. SEC GSH levels were more than 70% to 80% depleted by monocrotaline and azathioprine, respectively, before cell death. Azathioprine and monocrotaline are selectively toxic to SEC; the mechanism of toxicity in the SEC may be caused by profound GSH depletion.
导致肝静脉闭塞病（HVOD）的机制目前仍 largely 未知。作为一系列研究的一部分，对硫唑嘌呤和野百合碱进行了研究，这些研究涉及多种诱导 HVOD 的毒素，以寻找可能具有致病意义的共同特征。在先前的一项研究中，与肝细胞相比，达卡巴嗪在体外对肝血窦内皮细胞（SEC）表现出选择性毒性，并且证明了 SEC 谷胱甘肽（GSH）的关键作用。分离并在培养中研究了小鼠 SEC 和肝细胞。发现硫唑嘌呤和野百合碱对 SEC 的选择性毒性比对肝细胞更大。肝细胞对硫唑嘌呤的相对抗性归因于增强的 GSH 防御：暴露于硫唑嘌呤的肝细胞比 SEC 更好地维持细胞内 GSH 水平，特别是当添加补充性 GSH 前体时，并且细胞内 GSH 的消耗完全克服了肝细胞的抗性。相比之下，肝细胞中野百合碱的毒性在很大程度上不受 GSH 消耗的影响，这表明野百合碱对 SEC 的选择性可能归因于代谢激活的差异。两种化合物在 SEC 中均被 GSH 解毒，如在丁硫氨酸亚砜胺（BSO）存在下毒性增强以及外源性 GSH 使毒性减弱所证明。在细胞死亡前，野百合碱和硫唑嘌呤分别使 SEC 的 GSH 水平降低了 70%至 80%以上。硫唑嘌呤和野百合碱对 SEC 具有选择性毒性；SEC 中的毒性机制可能是由 GSH 的深度消耗引起的。
