Comparison of adriamycin uptake in chick embryo heart and liver cells an murine L5178Y lymphoblasts in vitro: role of drug uptake in cardiotoxicity.
Comparison of adriamycin uptake in chick embryo heart and liver cells an murine L5178Y lymphoblasts in vitro: role of drug uptake in cardiotoxicity.
复制标题
体外鸡胚心脏和肝细胞和小鼠 L5178Y 淋巴母细胞中阿霉素摄取的比较：药物摄取在心脏毒性中的作用。
作者：
B. A. Johnson;M. Cheang;G. Goldenberg
本文研究了阿霉素在鸡胚心肌细胞、肝细胞和小鼠L5178 Y淋巴母细胞中的摄取机制。由于快速结合，在4 ℃下持续15秒的药物摄取在心脏细胞中占104 +/- 14（SE）的细胞：培养基分布比，在肝细胞中为10.2 +/- 1.3，在L5178 Y淋巴母细胞中为10.3 +/- 1.5。在薄层色谱分析中，98%的放射性随完整药物的迁移率迁移，表明在心脏和肿瘤细胞中至少30 min内药物代谢可忽略不计。药物摄取的时间过程在心脏细胞中与在肝脏或L5178 Y细胞中观察到的时间过程有些不同。在心脏细胞中更迅速地达到药物摄取的稳态;在心脏细胞中在6 min时观察到表观平衡，在L5178 Y淋巴母细胞中在约20 min时观察到表观平衡，但在肝细胞中在25 min时未达到表观平衡。药物摄取的温度依赖性在三种细胞类型中也不同;药物摄取在L5178 Y细胞中是最温度敏感的，在肝细胞中是中间的，在心脏细胞中温度依赖性最小。心脏，肝脏和白血病细胞分离成膜和胞质溶胶部分表明，在1和30分钟，超过75%的药物与膜部分。细胞成分的三氯乙酸提取物显示，在1分钟时，酸溶性部分在心脏细胞中占放射性的32 +/- 2%，在L5178 Y细胞中占放射性的37 +/- 2%。这些细胞的乙醇提取物表明，在1分钟时，乙醇可溶性组分占心脏细胞放射性的49 +/- 2%，占白血病细胞放射性的27 +/- 2%。快速结合的大组分的发现以及药物与细胞组分迅速结合的证据使得单向药物流入的评价不切实际。因此，在细胞已经加载药物不同的时间间隔后，研究阿霉素从鸡胚心脏和肝脏细胞以及L5178 Y淋巴母细胞的流出。在所有三种细胞类型中，外排迅速下降至平台水平，代表不可交换药物。随着细胞加载时间的增加，不可交换药物的水平逐渐升高。在心脏细胞中，非交换池的平衡比在肝脏或白血病细胞中发生得更快。（400字处截断摘要）
The mechanism of uptake of Adriamycin was investigated in chick embryo heart and liver cells and in murine L5178Y lymphoblasts in vitro. Drug uptake at 4 degrees C for 15 s due to rapid association accounted for a cell:medium distribution ratio of 104 +/- 14 (SE) in heart cells, 10.2 +/- 1.3 in liver cells, and 10.3 +/- 1.5 in L5178Y lymphoblasts. On thin-layer chromatographic analysis, 98% of the radioactivity migrated with the mobility of intact drug, suggesting that drug metabolism was negligible for at least 30 min in both heart and tumor cells. A time course of drug uptake was somewhat different in heart cells compared to that noted for liver or L5178Y cells. The steady state for drug uptake was reached more promptly in heart cells; apparent equilibrium was observed at 6 min in heart cells, at approximately 20 min in L5178Y lymphoblasts, but was not attained by 25 min in liver cells. Temperature dependence of drug uptake also differed in the three cell types; drug uptake was most temperature sensitive in L5178Y cells, intermediate in liver cells, and least temperature dependent in heart cells. Separation of heart, liver, and leukemic cells into membrane and cytosol fractions demonstrated that, at 1 and 30 min, more than 75% of the drug was associated with the membrane fraction. Trichloroacetic acid extraction of cell constituents revealed that, at 1 min, the acid-soluble fraction amounted to 32 +/- 2% of radioactivity in heart cells and 37 +/- 2% in L5178Y cells. Ethanol extraction of these cells demonstrated that, at 1 min, ethanol-soluble components accounted for 49 +/- 2% of radioactivity in heart cells and 27 +/- 2% in leukemic cells. The finding of a large component of rapid association together with evidence of prompt drug binding to cellular constituents made evaluation of unidirectional drug influx impractical. Accordingly, an investigation was undertaken of Adriamycin efflux from chick embryo heart and liver cells and L5178Y lymphoblasts, after the cells had been loaded with drug for various time intervals. In all three cell types, efflux was rapid down to a plateau level, representing nonexchangeable drug. As the period of time for loading cells was increased, there was a progressive rise in the level of nonexchangeable drug. Equilibration of the nonexchangeable pool occurred more rapidly in heart cells than in either liver or leukemic cells.(ABSTRACT TRUNCATED AT 400 WORDS)