Steinfelder H J, Pethö-Schramm S
Institute of Pharmacology and Toxicology, University of Göttingen, F.R.G.
Biochem Pharmacol. 1990 Sep 1;40(5):1154-7. doi: 10.1016/0006-2952(90)90508-i.
In summary, this study characterized the biphasic inhibition of fat cell glucose transport by the lipolytic agents caffeine and theophylline. Like the lipolytic drug forskolin, both methylxanthines produced an immediate inhibition of glucose transport that was not seen with 8-phenyltheophylline, a pure adenosine receptor antagonist. The immediate inhibition was therefore not mediated by the adenosine receptor antagonism but seems to be due to a direct interaction with the hexose transporter. This conclusion is supported by the immediate onset of the inhibition and additionally by the interference of theophylline and caffeine with the binding of cytochalasin B, a ligand of the glucose transporter that binds to an intracellular site of the transporter molecule. In addition, a second, delayed inhibitory effect of theophylline and caffeine on glucose transport was observed. This portion shared many aspects of the inhibitory effect of lipolytic hormones. It developed over a period of about 5 min and was antagonized by the simultaneous addition of the antilipolytic hormone PGE2. This component of transport inhibition could be attributed to the antagonistic effect of methylxanthines at the fat cell A1-adenosine receptor since it was also seen with 8-phenyltheophylline. This conclusion is further supported by data showing that the removal of endogenous adenosine with adenosine deaminase resulted in a comparable 25-30% inhibition of insulin-stimulated glucose transport. In addition, the time course of glucose transport inhibition by the subsequent addition of adenosine deaminase is similar to that of the delayed portion of the inhibition seen with theophylline and caffeine. Both treatments produced their maximal inhibition after 5 min. In conclusion, the methylxanthines theophylline and caffeine inhibit glucose transport by a combination of two different modes of action. The immediate major component is mediated via a direct interaction with the hexose transporter whereas the delayed component involves adenosine receptor antagonism and thereby the interaction with G-proteins.
总之，本研究描述了脂解剂咖啡因和茶碱对脂肪细胞葡萄糖转运的双相抑制作用。与脂解药物福斯高林一样，这两种甲基黄嘌呤都能立即抑制葡萄糖转运，而纯腺苷受体拮抗剂8-苯基茶碱则不会出现这种情况。因此，这种即时抑制不是由腺苷受体拮抗作用介导的，似乎是由于与己糖转运体的直接相互作用。这一结论得到了抑制作用立即起效的支持，此外还得到了茶碱和咖啡因对细胞松弛素B结合的干扰的支持，细胞松弛素B是葡萄糖转运体的一种配体，可与转运体分子的细胞内位点结合。此外，还观察到茶碱和咖啡因对葡萄糖转运的第二种延迟抑制作用。这部分作用与脂解激素的抑制作用有许多共同之处。它在大约5分钟的时间内逐渐显现，并被同时添加的抗脂解激素前列腺素E2所拮抗。这种转运抑制成分可归因于甲基黄嘌呤对脂肪细胞A1-腺苷受体的拮抗作用，因为8-苯基茶碱也有同样的作用。数据进一步支持了这一结论，即使用腺苷脱氨酶去除内源性腺苷会导致胰岛素刺激的葡萄糖转运受到类似的25%-30%的抑制。此外，随后添加腺苷脱氨酶对葡萄糖转运的抑制时间进程与茶碱和咖啡因引起的延迟抑制部分相似。两种处理在5分钟后都产生了最大抑制作用。总之，甲基黄嘌呤茶碱和咖啡因通过两种不同的作用方式抑制葡萄糖转运。即时的主要成分是通过与己糖转运体的直接相互作用介导的，而延迟成分则涉及腺苷受体拮抗作用，从而与G蛋白相互作用。
