Cellular target of cyclophosphamide toxicity in the murine liver: Role of glutathione and site of metabolic activation
Cellular target of cyclophosphamide toxicity in the murine liver: Role of glutathione and site of metabolic activation
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DOI：
10.1002/hep.510240414
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发表时间：
1996-10-01
期刊：
影响因子：
13.5
通讯作者：
Huybrechts, MM
中科院分区：
文献类型：
--
作者：
DeLeve, LD;Wang, XD;Huybrechts, MM
肝静脉闭塞性疾病（HVOD）是由微循环障碍引起的，其机制尚不清楚。先前使用硫唑嘌呤、野百合碱和达卡巴嗪的体外研究表明，引起HVOD的毒素最初引起HVOD靶向窦状内皮细胞（SEC），可能是通过深刻的谷胱甘肽（GSH）消耗。目前的研究检查环磷酰胺在SEC和肝细胞中的毒性，以及两种细胞类型之间的相互作用。环磷酰胺对SEC没有直接毒性，但在SEC和肝细胞共培养中，环磷酰胺对SEC的毒性显著更大。两种环磷酰胺代谢产物，4-氢过氧环磷酰胺和丙烯醛，同样的毒性SEC，和毒性发生在20倍，低于肝细胞的浓度。4-在SEC中诱导细胞死亡之前，过氧化氢环磷酰胺消耗GSH超过95%。当肝细胞GSH水平持续补充蛋氨酸和丝氨酸共培养，在这两种细胞类型的毒性减少。在共培养中，SEC比肝细胞对环磷酰胺毒性明显更敏感，这可能是由肝细胞产生的丙烯醛引起的。与HVOD中涉及的其他毒素一样，SEC GSH的深度消耗先于毒性发作。SEC中诱导的环磷酰胺毒性程度由肝细胞中的代谢活化和GSH解毒决定。
Hepatic venoocclusive disease (HVOD) is caused by the disruption of the microcirculation by an as-yet unknown mechanism. Previous in vitro studies with azathioprine, monocrotaline, and dacarbazine suggested that toxins that cause HVOD initially causing HVOD target sinusoidal endothelial cells (SEC) perhaps via profound glutathione (GSH) depletion. The current study examines cyclophosphamide toxicity in SEC and hepatocytes, as well as the interplay between the two cell types. Cyclophosphamide was not directly toxic to SEC, but in coculture of SEC and hepatocytes, cyclophosphamide was significantly more toxic to SEC. Two cyclophosphamide metabolites, 4-hydroperoxycyclophosphamide and acrolein, were equally toxic to SEC, and toxicity occurred at 20-fold-lower concentrations than in hepatocytes. 4-Hydroperoxycyclophosphamide depleted GSH by greater than 95% before inducing cell death in SEC. When hepatocyte-GSH levels were sustained with supplemental methionine and serine in coculture, toxicity in both cell types was diminished. In coculture, SEC are significantly more susceptible than hepatocytes to cyclophosphamide toxicity, and this is likely caused by acrolein generated by the hepatocyte. As seen with other toxins implicated in HVOD, the profound depletion of SEC GSH precedes the onset of toxicity. The degree of cyclophosphamide toxicity induced in SEC is determined by both metabolic activation and GSH detoxification in the hepatocytes.