Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters.
Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters.
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DOI：
10.3389/fphar.2018.00510
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发表时间：
2018
影响因子：
5.6
通讯作者：
Zhang T
中科院分区：
文献类型：
--
作者：
Yi YX;Ding Y;Zhang Y;Ma NH;Shi F;Kang P;Cai ZZ;Zhang T
茵陈蒿汤（YCHD）是著名的中药方剂，用于治疗胆汁淤积已有数千年的历史。 YCHD的利胆作用已被广泛报道，但其药效学物质和潜在的治疗机制仍不清楚。采用超高效液相色谱（UHPLC）-四极杆飞行时间质谱联用技术，在大鼠口服YCHD后检测到11种原始活性成分和8种II期代谢物，其中包括3种新的II期代谢物。说明YCHD中大部分活性成分的主要代谢途径之一是II相代谢，与胆红素的代谢过程相似。 YCHD的代谢过程与其利胆作用是否有关系，这引起了我们的好奇。因此，我们开发了一种同时定量大黄酸、大黄素、京尼平和毛细血管素的八种活性成分和四种II相代谢物的新方法，并应用于正常和α-萘基异硫氰酸酯（ANIT）诱导的肝内胆汁淤积大鼠的药代动力学研究。结果表明，YCHD的大部分成分的药代动力学行为均受到抑制，推测这与大鼠肝脏中不同水平的代谢酶和转运蛋白有关。因此，通过UHPLC-串联质谱方法监测了胆汁淤积和YCHD治疗大鼠肝内酶表达的动态变化。结果显示，胆汁淤积大鼠中UDP-葡萄糖醛酸基转移酶1-1（UGT1A1）、有机阴离子转运多肽1A4（OATP1A4）、多药耐药相关蛋白2（MRP2）、多药耐药蛋白1、钠依赖性牛磺胆酸协同转运蛋白和有机阴离子转运多肽1A2的表达水平显着受到抑制，这可能是药物吸收和药物吸收减少的原因。胆汁淤积大鼠YCHD的代谢过程。高剂量（12 g/kg）YCHD显着增加胆汁淤积大鼠中UGT1A1、胆盐输出泵、MRP2、OATP1A4的表达，显示其对胆汁淤积表现出最大的改善作用，尤其是在组织病理学检查中，并降低丙氨酸转氨酶、天冬氨酸转氨酶、总胆红素、直接胆红素和总胆汁酸的水平。考虑到体内胆红素的代谢过程，YCHD的利胆作用被证明与其对胆汁淤积肝脏中代谢酶和转运蛋白表达的调节作用有关。
Yinchenhao Decoction (YCHD), a famous traditional Chinese formula, has been used for treating cholestasis for 1000s of years. The cholagogic effect of YCHD has been widely reported, but its pharmacodynamic material and underlying therapeutic mechanism remain unclear. By using ultra-high-performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry, 11 original active components and eight phase II metabolites were detected in rats after oral administration of YCHD, including three new phase II metabolites. And it indicated that phase II metabolism was one of the major metabolic pathway for most active components in YCHD, which was similar to the metabolism process of bilirubin. It arouses our curiosity that whether the metabolism process of YCHD has any relationship with its cholagogic effects. So, a new method for simultaneous quantitation of eight active components and four phase II metabolites of rhein, emodin, genipin, and capillarisin has been developed and applied for their pharmacokinetic study in both normal and alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis rats. The results indicated the pharmacokinetic behaviors of most components of YCHD were inhibited, which was hypothesized to be related to different levels of metabolic enzymes and transporters in rat liver. So dynamic changes of intrahepatic enzyme expression in cholestasis and YCHD treated rats have been monitored by an UHPLC-tandem mass spectrometry method. The results showed expression levels of UDP-glucuronosyltransferase 1-1 (UGT1A1), organic anion-transporting polypeptide 1A4 (OATP1A4), multidrug resistance-associated protein 2 (MRP2), multidrug resistance protein 1, sodium-dependent taurocholate cotransporter, and organic anion-transporting polypeptide 1A2 were significantly inhibited in cholestasis rats, which would account for reducing the drug absorption and the metabolic process of YCHD in cholestatic rats. A high dose (12 g/kg) of YCHD remarkably increased the expression of UGT1A1, bile salt export pump, MRP2, OATP1A4 in cholestasis rats presented it exhibited the greatest ameliorative effect on cholestasis, also particularly in histopathological examination and reducing levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, and total bile acid. Considering the metabolic process of bilirubin in vivo, the choleretic effect of YCHD is proven to be related to its regulatory action on expression of metabolic enzymes and transporters in cholestatic liver.
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影响因子：
3.8
作者：
CONNOLLY, AK;PRICE, SC;HINTON, RH
通讯作者：
HINTON, RH
影响因子：
3.8
作者：
Cui, Yue J.;Aleksunes, Lauren M.;Klaassen, Curtis D.
通讯作者：
Klaassen, Curtis D.
长期服用黄芩苷可改善高脂饮食大鼠的代谢紊乱和肝脂肪变性
影响因子：
8.2
作者：
Guo, Hong-xia;Liu, Dai-hua;Peng, Hong-li
通讯作者：
Peng, Hong-li
影响因子：
3.3
作者：
Bruschi, Maurizio;Candiano, Giovanni;Verrina, Enrico
通讯作者：
Verrina, Enrico
影响因子：
1.8
作者：
Ding, Yue;Zhang, Tong;Yang, Li
通讯作者：
Yang, Li