Mills C O, Milkiewicz P, Saraswat V, Elias E
Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom.
Yale J Biol Med. 1997 Jul-Aug;70(4):447-57.
There have been attempts to couple bile acids to fluorescein to permit their visualization during studies of physiology and pathophysiology. Although conjugation has been achieved by many, the product differed in many respects from the parent bile acid congener. We describe lysylfluorescein conjugated bile acid analogues (LFCBAA) synthesized in our laboratory as model divalent "unipolar" molecules. We have determined LFCBAA properties including their water:octanol partition coefficient, HPLC retention time and critical micellar concentration and compared them with their parent bile acid congeners. Cholyl lysylfluorescein (CLF) and lithocholyl lysylfluoroscein (LLF) have properties similar to cholylglycine (CG) and glycolithocholate (GLC), respectively. In human and rat hepatocytes uptake of CLF follows Michaelis-Menten kinetics with K(m) and Vmax similar to CG. Biliary excretion rates of CLF and LLF closely resemble those of CG and GLC in both normal and mutant TR- rats which lack the multiorganic anion transporter (MOAT), strongly supporting the notion that CLF and LLF are substrates for the canalicular bile salt transporter (cBST). The close similarity of hepatocyte uptake and biliary secretion of these LFCBAA and their parent bile acid congeners makes them potentially useful probes for the intracellular visualization of bile salt movement and deposition in various models of bile formation and secretion.
已有研究尝试将胆汁酸与荧光素偶联，以便在生理学和病理生理学研究中实现对其可视化观察。尽管许多研究都实现了这种偶联，但所得产物在许多方面与母体胆汁酸同系物存在差异。我们描述了在我们实验室合成的赖氨酰荧光素偶联胆汁酸类似物（LFCBAA），它们是作为二价“单极”分子模型。我们测定了LFCBAA的性质，包括其水：辛醇分配系数、高效液相色谱保留时间和临界胶束浓度，并将它们与其母体胆汁酸同系物进行了比较。胆酰赖氨酰荧光素（CLF）和石胆酰赖氨酰荧光素（LLF）的性质分别与胆酰甘氨酸（CG）和甘氨石胆酸（GLC）相似。在人和大鼠肝细胞中，CLF的摄取遵循米氏动力学，其K(m)和Vmax与CG相似。在缺乏多有机阴离子转运体（MOAT）的正常和突变TR - 大鼠中，CLF和LLF的胆汁排泄率与CG和GLC的非常相似，这有力地支持了CLF和LLF是胆小管胆汁盐转运体（cBST）底物的观点。这些LFCBAA与其母体胆汁酸同系物在肝细胞摄取和胆汁分泌方面的高度相似性，使其有可能成为在各种胆汁形成和分泌模型中对胆汁盐运动和沉积进行细胞内可视化观察的有用探针。
