Chitrawina MahagitaKhwanchit TanphichaiApichart SuksamrarnNazzareno BallatoriPawinee PiyachaturawatMahidol UniversityUniversity of RochesterRamkhamhaeng University2018-08-202018-08-202006-11-01Pharmaceutical Research. Vol.23, No.11 (2006), 2603-26101573904X072487412-s2.0-33750633666https://repository.li.mahidol.ac.th/handle/20.500.14594/23143Purpose. 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. Methods. 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. Results. 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 HCO3-, 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-β- 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. Conclusions. These results demonstrate that the major biliary metabolite of 4-HA in rats is the 4-O-β-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. © 2006 Springer Science+Business Media, LLC.Mahidol UniversityChemistryPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1007/s11095-006-9097-z