Wang Wei, Ren Xiaofei, Cai Yi, Chen Lihong, Zhang Weiping, Xu Jianming
Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei, 230022, Anhui Province, China.
Dig Dis Sci. 2016 Jan;61(1):126-36. doi: 10.1007/s10620-015-3850-2. Epub 2015 Aug 29.
Previous studies have shown that rifampicin induced choleresis, the mechanisms of which have not been described. The aim of this study was to investigate the mechanisms underlying in vivo rifampicin-induced choleresis.
In one experimental set, rats were treated chronically with rifampicin on days 1, 3 and 7. Serum and biliary parameters were assayed, and mRNA and protein levels, as well as the locations of the hepatic export transporters were analyzed by real-time PCR, western blot and immunofluorescence. Ductular mass was evaluated immunohistochemically. In another experimental set, rats received an acute infusion of rifampicin. The amount of rifampicin in bile was detected using HPLC. Biliary parameters were monitored following intrabiliary retrograde fluxes of the Cl(-)/HCO3 (-) exchange inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) in the infused rats.
Biliary bicarbonate output increased in parallel to the augmented bile flow in response to rifampicin, and this effect was abolished with intrabiliary administration of DIDS, but not NPPB. The biliary secretion of rifampicin with increases in bile flow and biliary rifampicin in response to different infused doses of the antibiotic show no significant correlations. After rifampicin treatment, the expression level of anion exchanger 2 (AE2) increased, while the location of hepatic transporters did not change. However, RIF treatment did not increase ductular mass significantly.
These results indicate that the increase in bile flow induced by rifampicin is mainly due to increased HCO3 (-) excretion mediated by increased AE2 protein expression and activity.
既往研究表明利福平可诱导胆汁分泌，但其机制尚未阐明。本研究旨在探讨利福平在体内诱导胆汁分泌的机制。
在一组实验中，于第1、3和7天对大鼠进行利福平长期治疗。检测血清和胆汁参数，通过实时PCR、蛋白质印迹和免疫荧光分析肝转运蛋白的mRNA和蛋白质水平及其定位。采用免疫组织化学方法评估胆管增生。在另一组实验中，对大鼠进行利福平急性输注。使用高效液相色谱法检测胆汁中利福平的含量。在输注大鼠中，经胆管逆行注入Cl(-)/HCO3 (-)交换抑制剂4,4'-二异硫氰基芪-2,2'-二磺酸（DIDS）或5-硝基-2-(3-苯丙基氨基)苯甲酸（NPPB）后，监测胆汁参数。
利福平诱导胆汁分泌增加的同时，胆汁中碳酸氢盐排出量也相应增加，经胆管给予DIDS可消除此效应，但NPPB无效。不同输注剂量抗生素作用下，利福平的胆汁分泌量增加与胆汁流量和胆汁中利福平增加无显著相关性。利福平治疗后，阴离子交换蛋白2（AE2）表达水平升高，而肝转运蛋白的定位未改变。然而，利福平治疗并未显著增加胆管增生。
这些结果表明，利福平诱导的胆汁流量增加主要是由于AE2蛋白表达和活性增加介导的HCO3 (-)排泄增加所致。
