在肝和肠体外细胞模型中，奥贝胆酸和天然胆汁酸对FXR的比较效力。,Pharmacology Research & Perspectives

当前位置： X-MOL 学术 › Pharmacol. Res. Perspect. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

在肝和肠体外细胞模型中，奥贝胆酸和天然胆汁酸对FXR的比较效力。
Pharmacology Research & Perspectives ( IF 2.9 ) Pub Date : 2017-12-12 , DOI: 10.1002/prp2.368
Yuanyuan Zhang ₁ , Carl LaCerte ₁ , Sanjay Kansra ₁ , Jonathan P Jackson ₂ , Kenneth R Brouwer ₂ , Jeffrey E Edwards ₁

Affiliation

奥贝胆酸（OCA）是一种半合成的法尼醇X受体（FXR）激动剂，是鹅去氧胆酸（CDCA）的类似物，可与熊去氧胆酸（UDCA）结合治疗原发性胆源性胆管炎（PBC）。OCA通过激活FXR介导的生理相关的体外细胞系统（夹心培养的Transporter Certified™人类原代肝细胞（SCHH））中的FXR介导的机制，有效抑制胆汁酸的合成并促进胆汁酸的外流。本文的研究评估了UDCA单独或与OCA联合在SCHH中的作用。单独的UDCA（≤100μmol/ L）不会抑制CYP7A1 mRNA，因此，未观察到内源性胆汁酸池减少。UDCA≤100μmol/ L与0.1μmol/ L的OCA并用时，对胆汁酸的合成没有影响，超过了单独使用OCA所观察到的。此外，这项研究评估了人类Caco-2细胞（克隆C2BBe1）作为体外肠道模型。OCA的甘氨酸偶联物以浓度依赖性方式增加Caco-2细胞，FGF-19，SHP，OSTα/β和IBABP中FXR靶基因的mRNA水平，而不是ASBT，而浓度依赖性。这些基因的表达。结果表明，UDCA≤100μmol/ L不会激活人原代肝细胞或肠细胞Caco-2中的FXR。因此，UDCA与OCA并用不会影响OCA依赖性药理作用。UDCA的甘氨酸偶联物对这些基因的表达没有影响。结果表明，UDCA≤100μmol/ L不会激活人原代肝细胞或肠细胞Caco-2中的FXR。因此，UDCA与OCA并用不会影响OCA依赖性药理作用。UDCA的甘氨酸偶联物对这些基因的表达没有影响。结果表明，UDCA≤100μmol/ L不会激活人原代肝细胞或肠细胞Caco-2中的FXR。因此，UDCA与OCA并用不会影响OCA依赖性药理作用。

"点击查看英文标题和摘要"

Comparative potency of obeticholic acid and natural bile acids on FXR in hepatic and intestinal in vitro cell models.

Obeticholic acid (OCA) is a semisynthetic farnesoid X receptor (FXR) agonist, an analogue of chenodeoxycholic acid (CDCA) which is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA). OCA efficiently inhibits bile acid synthesis and promotes bile acid efflux via activating FXR-mediated mechanisms in a physiologically relevant in vitro cell system, Sandwich-cultured Transporter Certified ™ human primary hepatocytes (SCHH). The study herein evaluated the effects of UDCA alone or in combination with OCA in SCHH. UDCA (≤100 μmol/L) alone did not inhibit CYP7A1 mRNA, and thus, no reduction in the endogenous bile acid pool observed. UDCA ≤100 μmol/L concomitantly administered with 0.1 μmol/L OCA had no effect on bile acid synthesis beyond what was observed with OCA alone. Furthermore, this study evaluated human Caco-2 cells (clone C2BBe1) as in vitro intestinal models. Glycine conjugate of OCA increased mRNA levels of FXR target genes in Caco-2 cells, FGF-19, SHP, OSTα/β, and IBABP, but not ASBT, in a concentration-dependent manner, while glycine conjugate of UDCA had no effect on the expression of these genes. The results suggested that UDCA ≤100 μmol/L did not activate FXR in human primary hepatocytes or intestinal cell line Caco-2. Thus, co-administration of UDCA with OCA did not affect OCA-dependent pharmacological effects.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文