Plasma membrane changes of liver and Morris hepatoma induced by retinol in rats.
Plasma membrane changes of liver and Morris hepatoma induced by retinol in rats.
复制标题
视黄醇诱导大鼠肝脏和莫里斯肝癌质膜变化。
作者：
R. Büchsel;W. Reutter
摘要p.o.-给药标记的全反式视黄醇在体内进行了研究，在大鼠携带9种不同类型的莫里斯肝癌。在血清、肝脏和相应肿瘤的酸沉淀和酸溶性部分中发现放射性。在不同类型的Morris肝癌中，发现视黄醇的摄取减少。根据其生长速率，肿瘤蓄积了相应宿主肝脏中测定的放射性的1.6%至50%。当增加的生长速率与维生素的减少的吸收速率作图时，得到线性相关。显然，视黄醇摄取减少是Morris肝癌的共同特征，似乎与恶性转化有关，而与生长增加无关，因为在再生肝中，p.o.-大剂量（1.5 × 106 IU/kg体重）视黄醇引起的肝细胞质膜组分中岩藻蛋白代谢的主要变化是标记的L-岩藻糖掺入率降低67%，同时蛋白结合的L-岩藻糖周转增加。蛋白结合的l-岩藻糖的半衰期为23小时，在视黄醇治疗的大鼠，而在配对喂养的对照动物，它是41小时。然而，在胞质部分，蛋白结合的l-岩藻糖的半衰期增加，从36小时至110小时，通过喂养视黄醇。蛋白质合成的视黄醇治疗大鼠标记的l-蛋氨酸掺入测量不变，在肝脏，肝癌，血清蛋白在第一个小时后的脉冲。然而，2小时后的L-蛋氨酸脉冲，观察到的掺入率的额外增加。质膜多肽的荧光分析揭示了标记模式的特征性变化后，在体内与L-岩藻糖标记。这些改变包括在30，000至220，000的表观分子量范围内的谱带的位移。在Morris肝癌9121的质膜组分中，仅观察到轻微的变化，尽管在喂食1.5 × 106 IU/kg体重后24小时，在肿瘤中发现70 IU/mg蛋白质的维生素A。这项研究表明，高剂量的视黄醇后，肝脏分泌活动增加，导致质膜不完全岩藻糖基化的糖蛋白的快速周转。随后的糖基化模式的改变，如通过在体内用l-岩藻糖标记所揭示的，在肿瘤质膜中是检测不到的。因此，肿瘤细胞质膜不是视黄醇的主要靶细胞器。可能是宿主的变化而不是肿瘤本身的变化导致了视黄醇和类维生素A的抗癌作用。
Abstract The uptake and binding of p.o.-administered labeled all- trans -retinol was studied in vivo in rats bearing nine different types of Morris hepatomas. Radioactivity was found in acid-precipitable and acid-soluble fractions of serum, liver, and the respective tumor. In the different types of Morris hepatomas, the uptake of retinol was found to be decreased. Depending on their growth rates, the tumors accumulated 1.6 to 50% of the radioactivity determined in the respective host liver. A linear correlation was obtained when the increasing growth rates were plotted logarithmically versus the decreasing uptake rates of the vitamin. Evidently, the decreased uptake of retinol is a common feature of Morris hepatomas and seems to be related to malignant transformation and not to increased growth, because in the regenerating liver an increase of the uptake of p.o.-administered retinol was found. A 67% decrease in the incorporation rate of labeled l-fucose and a simultaneously increased turnover of protein-bound l-fucose were the major alterations of the fucoprotein metabolism in the plasma membrane fraction of the liver induced by high doses of retinol (1.5 × 10 6 IU all- trans -retinol per kg of body weight). The half-life of protein-bound l-fucose was 23 hr in retinol-treated rats, whereas in pair-fed control animals it was 41 hr. However, in the cytosolic fraction, the half-life of protein-bound l-fucose increased from 36 hr to 110 hr by feeding retinol. Protein synthesis in retinol-treated rats measured by labeled l-methionine incorporation was unchanged in liver, hepatoma, and serum protein during the first hr after the pulse. However, 2 hr after the l-methionine pulse, an additional increase of the incorporation rate was observed. Fluorographic analysis of the plasma membrane polypeptides revealed characteristic changes in the labeling pattern after labeling with l-fucose in vivo . These alterations comprise shifts of bands in the apparent molecular weight range of 30,000 to 220,000. In the plasma membrane fraction of Morris hepatoma 9121, only minimal changes were seen, although 70 IU of vitamin A per mg protein were found in the tumor 24 hr after feeding 1.5 × 10 6 IU/kg of body weight. This study indicates that the increased hepatic secretory activity after high doses of retinol leads to rapid turnover of incompletely fucosylated glycoproteins of the plasma membrane. The subsequent alterations in the glycosylation pattern as revealed by labeling with l-fucose in vivo are not detectable in the tumor plasma membrane. Therefore, the tumor plasma membrane is not the main target organelle of retinol. Possibly, changes in the host rather than in the tumor itself may be responsible for the anticarcinogenic effect of retinol and the retinoids.