RGD Reference Report - 4-Hydroxyacetophenone-induced choleresis in rats is mediated by the Mrp2-dependent biliary secretion of its glucuronide conjugate. - Rat Genome Database

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

Authors: Mahagita, C  Tanphichai, K  Suksamrarn, A  Ballatori, N  Piyachaturawat, P 
Citation: Mahagita C, etal., Pharm Res. 2006 Nov;23(11):2603-10. Epub 2006 Sep 29.
RGD ID: 11081011
Pubmed: PMID:17009103   (View Abstract at PubMed)
DOI: DOI:10.1007/s11095-006-9097-z   (Journal Full-text)

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 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ABCC2Humancholestasis  ISOAbcc2 (Rattus norvegicus) RGD 
Abcc2Ratcholestasis  IMP  RGD 
Abcc2Mousecholestasis  ISOAbcc2 (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcc2  (ATP binding cassette subfamily C member 2)

Genes (Mus musculus)
Abcc2  (ATP-binding cassette, sub-family member 2)

Genes (Homo sapiens)
ABCC2  (ATP binding cassette subfamily C member 2)


Additional Information