Hepatotrophic properties in dogs of human FKBP, the binding protein for FK506 and rapamycin.
Hepatotrophic properties in dogs of human FKBP, the binding protein for FK506 and rapamycin.
复制标题
人 FKBP（FK506 和雷帕霉素的结合蛋白）对狗的保肝特性。
DOI：
10.1097/00007890-199110000-00038
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发表时间：
1991
期刊：
影响因子：
6.2
通讯作者：
Francavilla,A
中科院分区：
文献类型：
--
作者：
Starzl,TE;Schreiber,SL;Albers,MW;Porter,KA;Foglieni,CS;Francavilla,A
两个实验模型已显示环孢素和 FK506 可以影响肝脏的结构、功能和再生能力。这两种药物都能增强大鼠的肝脏再生，这是对部分肝切除术的正常反应 (1)。此外，通过结扎的中央门静脉肝内输注这些药物，使犬门腔分流术引起的肝细胞复制增加一倍以上。此外，还可以防止门静脉分流引起的萎缩和细胞器破坏 (2, 3)。淋巴细胞和 NK 细胞的免疫调节作为这些所谓“肝营养”效应的解释已被裸鼠直接实验排除 (4)。 上述发现，以及对接受 FK506 或环孢素治疗的患者的多种代谢效应的观察，得出了这样一个假设：这些药物改变了多种细胞的信号转导，而不仅限于免疫系统的信号转导 (3, 5)。与该假设一致的是最近的证明，FK506 和环孢菌素抑制肥大细胞中信号传导过程的浓度与用于阻断 T 细胞信号传导途径的浓度相似（6；还有 Schreiber SL 等人，未发表的观察结果）。信号转导假说的核心是发现 FK506 和雷帕霉素（FK506 结合蛋白，FKBP）* 和环孢菌素（亲环蛋白）的胞质受体是具有肽基脯氨酰顺反异构酶（旋转异构酶）活性的不同蛋白质 (7, 8)。旋转异构酶已被证明可促进蛋白质折叠 (9, 10) 并在体外催化肽基-脯氨酰键旋转异构体的相互转化 (11, 12)。然而，这种酶活性的抑制与这些药物在 T 细胞 (13) 或肥大细胞中的作用无关（Schreiber SL、Hohman RJ 等人，未发表的观察结果）。相反，这些蛋白质被认为是一类小分子量细胞质蛋白（统称为亲免素）的成员，它们通过与免疫抑制药物形成复合物来调节多种钙依赖性信号转导途径 (13, 14)。通过免疫细胞化学技术检测到体内几乎所有细胞的细胞质以及某些细胞的细胞核中亲环蛋白的普遍分布，强调了亲免蛋白网络的潜在重要性和多效性(15, 16)。
Cyclosporine and FK506 have been shown with two experimental models to influence liver structure, function, and the capacity for regeneration. Both drugs augment the liver regeneration in rats that is the normal response to partial hepatectomy (1). In addition, the increase in hepatocyte replication that is caused by portacaval shunt in dogs is more than doubled by intrahepatic infusion of these drugs via the tied-off central portal vein. Also, the atrophy and organelle disruption caused by portacaval shunt is prevented (2, 3). Immune modulation of lymphocytes and NK cells as an explanation for these so-called “hepatotrophic” effects has been ruled out by direct experimentation in nude rats (4).The foregoing findings, as well as observations of manifold metabolic effects in patients treated either with FK506 or with cyclosporine, have led to a hypothesis that these drugs modify signal transduction in a variety of cells, not limited to those of the immune system (3, 5). Consistent with the hypothesis is the recent demonstration that FK506 and cyclosporine inhibit signaling processes in the mast cell at concentrations similar to those used to block signaling pathways in T cells (6; also Schreiber SL, et al., unpublished observations). Central to the signal transduction hypothesis was the discovery that the cytosolic receptors for FK506 and rapamycin (FK506-binding protein, FKBP)* and cyclosporine (cyclophilin) are distinct proteins that exhibit peptidyl-prolyl cis trans isomerase (rotamase) activity (7, 8). Rotamases have been shown to facilitate protein folding (9, 10) and to catalyze the interconversion of rotamers of peptidyl-prolyl bonds in vitro (11, 12). However, the inhibition of this enzymatic activity is not related to the action of these drugs in the T cell (13) or the mast cell (Schreiber SL, Hohman RJ, et al., unpublished observations). Instead, these proteins are envisioned as members of a class of small molecular weight cytoplasmic proteins (collectively called immunophilins) that modulate a wide variety of calcium-dependent signal transduction pathways by forming complexes with immunosuppressive drugs (13, 14). The potential importance and pleiotropism of the immunophilin network is emphasized by the ubiquitous distribution of cyclophilin as detected by immunocytochemical techniques in the cytoplasm of virtually all cells in the body, and in the nuclei of some (15, 16).