Inhibition of the intestinal absorption of bile acids using cationic derivatives: Mechanism and repercussions
Inhibition of the intestinal absorption of bile acids using cationic derivatives: Mechanism and repercussions
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DOI：
10.1016/j.bcp.2006.10.014
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发表时间：
2007-02-01
影响因子：
5.8
通讯作者：
Marin, Jose J. G.
中科院分区：
文献类型：
--
作者：
Vicens, Marta;Macias, Rocio I. R.;Marin, Jose J. G.
为了有效阻断胆汁酸的肝肠循环，将N-（3-氨丙基）-1，3-丙二胺与甘氨胆酸（GC）的一个或两个部分偶联，得到两个带1或2个正电荷的甾体结构化合物BAPA-3和BAPA-6。BAPA-3和BAPA-6抑制Na+依赖的牛磺胆酸（TC）的非洲爪蟾卵母细胞表达大鼠Asbt的摄取，K-i值分别为28和16 μ M。BAPA-3降低Va而不影响Km。相反，BAPA-6增加K-m，对V-max没有影响。未标记的GC、BAPA-3和BAPA-6对大鼠回肠（原位灌注60 min）最后10 cm处的[C-14]-GC摄取的抑制程度相似。然而，这些化合物的肠吸收比GC低（BAPA-6）或低得多（BAPA-3）。当口服给予小鼠时，两种化合物（BAPA-3 > BAPA-6）都降低了胆汁酸池的大小，这伴随着肝Cyp 7a 1和Hmgcr以及肠Ost α/Ost β的上调。还观察到肝Ntcp表达降低和肠Asbt表达增强的趋势。血清生化参数没有受到这些化合物治疗的影响，除了血清甘油三酯浓度的中度增加。总之，我们的研究结果表明，这些化合物，特别是BAPA-3，是潜在的有用的工具，抑制肠道吸收胆汁酸的非竞争性方式。(c)2006年爱思唯尔公司All rights reserved.
To pharmacologically interrupt bile acid enterohepatic circulation, two compounds named BAPA-3 and BAPA-6, with a steroid structure and 1 or 2 positive charges, were obtained by conjugation of N-(3-aminopropyl)-1,3-propanediamine with one or two moieties of glycocholic acid (GC). Both BAPA-3 and BAPA-6 inhibited Na+-dependent taurocholate (TC) uptake by Xenopus laevis oocytes expressing rat Asbt, with K-i values of 28 and 16 mu M, respectively. BAPA-3 reduced V a without affecting Km. In contrast, BAPA-6 increased K-m, with no effect on V-max. Uptake of [C-14]-GC by the last 10 cm of the rat ileum, perfused in situ over 60 min, was inhibited to a similar extent by unlabeled GC, BAPA-3 and BAPA-6. However, the intestinal absorption of these compounds was lower (BAPA-6) or much lower (BAPA-3) than that of GC. When administered orally to mice, both compounds (BAPA-3 > BAPA-6) reduced the bile acid pool size, which was accompanied by up-regulation of hepatic Cyp7a1 and Hmgcr and intestinal Ost alpha/Ost beta. A tendency towards a decreased expression of hepatic Ntcp and an enhanced expression of intestinal Asbt was also observed. Serum biochemical parameters were not affected by treatment with these compounds, except for a moderate increase in serum triglyceride concentrations. In sum, our results suggest that these compounds, in particular BAPA-3, are potentially useful tools for inhibiting the intestinal absorption of bile acids in a non-competitive manner. (c) 2006 Elsevier Inc. All rights reserved.