Anticholestatic Effects of Bezafibrate in Patients with Primary Biliary Cirrhosis Treated with Ursodeoxycholic Acid
Anticholestatic Effects of Bezafibrate in Patients with Primary Biliary Cirrhosis Treated with Ursodeoxycholic Acid
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DOI：
10.1002/hep.26018
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发表时间：
2013-05-01
期刊：
影响因子：
13.5
通讯作者：
Matsuzaki, Yasushi
中科院分区：
文献类型：
--
作者：
Honda, Akira;Ikegami, Tadashi;Matsuzaki, Yasushi
贝扎贝特是一种广泛使用的降血脂药物，被认为是过氧化物酶体增殖物激活受体（PPARs）的配体。最近，这种药物被认为是一种潜在的抗胆汁淤积药物，用于治疗对熊去氧胆酸（UDCA）单药反应不充分的原发性胆汁性肝硬化（PBC）。本研究的目的是通过分析PBC患者的血脂生物标志物以及基于细胞的酶和基因表达分析来探索贝扎贝特的抗胆固醇机制。19例早期PBC患者对UDCA （600 mg/天）单药治疗生化反应不完全，采用相同剂量的UDCA加贝扎布特（400 mg/天）治疗3个月。贝扎贝特治疗后，患者血清胆道酶、免疫球蛋白M （IgM）、胆固醇和甘油三酯浓度均有显著改善，胆汁酸合成标志物7 - α -羟基-4-胆固醇-3- 1 （C4）降低，CYP3A4/5活性标志物4- β -羟基胆固醇升高。人肝癌细胞系的体外实验表明，贝扎布特可以控制PPAR α和妊娠X受体（PXR）的靶基因；下调CYP7A1、CYP27A1和窦状Na+/牛磺胆酸共转运多肽（NTCP），上调CYP3A4、小管多药耐药蛋白3 （MDR3）、MDR1和多药耐药相关蛋白2 （MRP2）。结论：Bezafibrate是一种双PPARs/PXR激动剂，对UDCA单药生化反应不完全的早期PBC患者具有有效的抗胆碱抑制作用。(肝脏病学57:1931 2013;1941)
Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator-activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell-based enzymatic and gene expression assays. Nineteen patients with early-stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7 alpha-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and increase of 4 beta-hydroxycholesterol, a marker of CYP3A4/5 activity, were observed. In vitro experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPAR alpha, as well as those of the pregnane X receptor (PXR); down-regulating CYP7A1, CYP27A1, and sinusoidal Na+/taurocholate cotransporting polypeptide (NTCP), and up-regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance-associated protein 2 (MRP2). Conclusion: Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early-stage PBC patients with an incomplete biochemical response to UDCA monotherapy. (HEPATOLOGY 2013;57:1931-1941)