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|Title:||4-Hydroxyacetophenone-induced choleresis in rats is mediated by the Mrp2-dependent biliary secretion of its glucuronide conjugate|
University of Rochester
|Keywords:||Chemistry;Pharmacology, Toxicology and Pharmaceutics|
|Citation:||Pharmaceutical Research. Vol.23, No.11 (2006), 2603-2610|
|Abstract:||Purpose. 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.|
|Appears in Collections:||Scopus 2006-2010|
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