4-Hydroxyacetophenone-induced choleresis in rats is mediated by the Mrp2-dependent biliary secretion of its glucuronide conjugate.
OBJECTIVE
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 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.


CONCLUSIONS
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.
Mahagita
Chitrawina
C
Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Bangkok 10400, Thailand.
Tanphichai
Khwanchit
K
Suksamrarn
Apichart
A
Ballatori
Nazzareno
N
Piyachaturawat
Pawinee
P
D000098:Acetophenones / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000378:metabolism; D020719:Glucuronides / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000502:physiology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000098:Acetophenones; D002756:Cholagogues and Choleretics; D004573:Electrolytes; D020719:Glucuronides; D005978:Glutathione; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C031335:4-hydroxyacetophenone