Takikawa H, Sugiyama Y, Fernandez-Checa J C, Kuhlenkamp J, Ookhtens M, Kaplowitz N
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Hepatology. 1996 Jun;23(6):1642-9. doi: 10.1002/hep.510230647.
We previously identified that Y' bile acid binders (3alpha-hydroxysteroid dehydrogenases) interact with bile acids in intact rat hepatocytes using [3beta-3H, C24-14C]bile acids and that indomethacin, a competitive inhibitor of 3alpha-hydroxysteroid dehydrogenase, inhibits 3H-loss from the C3-position of bile acids as well as inhibits hepatic bile acid removal and excretion. To study the kinetics of these inhibitory effects, glycocholate transport was studied in the absence and presence of indomethacin in the single-pass perfused rat liver. Indomethacin decreased net hepatic glycocholate uptake in the perfused liver, which was confirmed in isolated hepatocytes and basolateral liver plasma membrane vesicles. However, indomethacin markedly increased the sinusoidal efflux and decreased the biliary excretion of glycocholate in the perfused liver. These observations indicate that the effect of indomethacin to delay biliary glycocholate excretion is related to either intracellular or canalicular glycocholate transport. The latter possibility seemed unlikely because indomethacin did not inhibit electrogenic or adenosine triphosphate (ATP)-dependent glycocholate uptake by canalicular liver plasma membrane vesicles. Thus, the current data support an important role for binding of bile acids to cytosolic proteins in overall hepatic transport and suggest that specific interference with cytosolic binding can interfere with the excretion of bile acids.
我们之前利用[3β-³H，C24-¹⁴C]胆汁酸确定了Y'胆汁酸结合剂（3α-羟基类固醇脱氢酶）在完整的大鼠肝细胞中与胆汁酸相互作用，并且吲哚美辛，一种3α-羟基类固醇脱氢酶的竞争性抑制剂，抑制胆汁酸C3位的³H丢失以及抑制肝脏胆汁酸的清除和排泄。为了研究这些抑制作用的动力学，在单通道灌注大鼠肝脏中，分别在不存在和存在吲哚美辛的情况下研究了甘氨胆酸盐的转运。吲哚美辛降低了灌注肝脏中肝脏对甘氨胆酸盐的净摄取，这在分离的肝细胞和基底外侧肝细胞膜囊泡中得到了证实。然而，吲哚美辛显著增加了灌注肝脏中甘氨胆酸盐的窦状隙流出并减少了其胆汁排泄。这些观察结果表明，吲哚美辛延迟胆汁中甘氨胆酸盐排泄的作用与细胞内或胆小管甘氨胆酸盐转运有关。后一种可能性似乎不大，因为吲哚美辛并不抑制胆小管肝细胞膜囊泡对甘氨胆酸盐的电致性或三磷酸腺苷（ATP）依赖性摄取。因此，目前的数据支持胆汁酸与胞质蛋白结合在肝脏整体转运中起重要作用，并表明对胞质结合的特异性干扰可干扰胆汁酸的排泄。
