Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides.
Mol Pharmacol
; 72(2): 387-94, 2007 Aug.
Article
em En
| MEDLINE
| ID: mdl-17485564
ABSTRACT
Glucuronidation is a major hepatic detoxification pathway for endogenous and exogenous compounds, resulting in the intracellular formation of polar metabolites that require specialized transporters for elimination. Multidrug resistance proteins (MRPs) are expressed in the liver and can transport glucuronosyl-conjugates. Using morphine as a model aglycone, we demonstrate that morphine-3-glucuronide (M3G), the predominant metabolite, is transported in vitro by human MRP2 (ABCC2), a protein present in the apical membrane of hepatocytes. Loss of biliary M3G secretion in Mrp2(-/-) mice results in its increased sinusoidal transport that can be attributed to Mrp3. Combined loss of Mrp2 and Mrp3 leads to a substantial accumulation of M3G in the liver, from which it is transported across the sinusoidal membrane at a low rate, resulting in the prolonged presence of M3G in plasma. Our results show that murine Mrp2 and Mrp3 provide alternative routes for the excretion of a glucuronidated substrate from the liver in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana Transportadoras
/
Proteínas Associadas à Resistência a Múltiplos Medicamentos
/
Fígado
/
Derivados da Morfina
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Pharmacol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Holanda