Mahagita Chitrawina, Tanphichai Khwanchit, Suksamrarn Apichart, Ballatori Nazzareno, Piyachaturawat Pawinee
Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Bangkok 10400, Thailand.
Pharm Res. 2006 Nov;23(11):2603-10. doi: 10.1007/s11095-006-9097-z. Epub 2006 Sep 29.
The present study examined the underlying mechanism by which 4-hydroxyacetophenone (4-HA), a bioactive compound found in several medicinal herbs, exerts its potent stimulatory effects on hepatic bile secretion.
Bile flow, and biliary excretion of 4-HA, its metabolites, and inorganic electrolytes was examined in both normal Wistar rats and in TR(-) Wistar rats that have a congenital defect in the multidrug resistance-associated protein-2, Mrp2/Abcc2. The effects of 4-HA were also examined in animals treated with buthionine sulfoximine to decrease hepatic glutathione (GSH) levels.
In normal rats, 4-HA dramatically increased bile flow rate, whereas it failed to exert a choleretic effect in TR(-) rats. This choleresis was not explained by increased biliary output of Na(+), K(+), Cl(-) or HCO(3) (-), or by increased biliary GSH excretion. Depletion of hepatic GSH with buthionine sulfoximine had no effect on the 4-HA-induced choleresis. HPLC analysis revealed that a single major compound was present in bile, namely.4-hydroxyacetophenone-4-O-beta-glucuronide, and that the parent compound was not detected in bile. Biliary excretion of the glucuronide was directly correlated with the increases in bile flow. In contrast to normal rats, this 4-HA metabolite was not present in bile of TR(-) rats.
These results demonstrate that the major biliary metabolite of 4-HA in rats is the 4-O-beta-glucuronide, a compound that is secreted into bile at high concentrations, and may thus account in large part for the choleretic effects of 4-HA. Transport of this metabolite across the canalicular membrane into bile requires expression of the Mrp2 transport protein.
本研究探讨了4-羟基苯乙酮（4-HA），一种存在于多种药草中的生物活性化合物，对肝脏胆汁分泌产生强效刺激作用的潜在机制。
在正常Wistar大鼠和多药耐药相关蛋白2（Mrp2/Abcc2）存在先天性缺陷的TR（-）Wistar大鼠中，检测胆汁流量以及4-HA及其代谢产物和无机电解质的胆汁排泄情况。还在经丁硫氨酸亚砜胺处理以降低肝脏谷胱甘肽（GSH）水平的动物中检测了4-HA的作用。
在正常大鼠中，4-HA显著增加胆汁流速，而在TR（-）大鼠中未能发挥利胆作用。这种利胆作用不能通过Na（+）、K（+）、Cl（-）或HCO（3）（-）的胆汁输出增加或胆汁GSH排泄增加来解释。用丁硫氨酸亚砜胺耗尽肝脏GSH对4-HA诱导的利胆作用没有影响。高效液相色谱分析显示胆汁中存在一种单一的主要化合物，即4-羟基苯乙酮-4-O-β-葡萄糖醛酸苷，并且在胆汁中未检测到母体化合物。葡萄糖醛酸苷的胆汁排泄与胆汁流量的增加直接相关。与正常大鼠相反，这种4-HA代谢产物在TR（-）大鼠的胆汁中不存在。
这些结果表明，大鼠中4-HA的主要胆汁代谢产物是4-O-β-葡萄糖醛酸苷，该化合物以高浓度分泌到胆汁中，因此可能在很大程度上解释了4-HA的利胆作用。这种代谢产物通过胆小管膜转运到胆汁中需要Mrp2转运蛋白表达。
