Influence of Verapamil and Cyclosporin A on bile acid metabolism and transport in rat liver slices.
Exp Toxicol Pathol
; 58(1): 31-7, 2006 Aug.
Article
em En
| MEDLINE
| ID: mdl-16793245
ABSTRACT
Verapamil (V) is a specific inhibitor of the P-glycoprotein (mdr1) in the hepatocyte canalicular membrane. Cyclosporin A (CsA) as an essential immunosuppressive drug has potentially cholestatic adverse effects on the liver, but increases the expression of mdr1. In precision-cut liver slices from 34- to 40-day-old male Wistar rats 26 individual free and conjugated bile acids (BAs) as markers of hepatic transport and synthesis function were analysed after 4 h incubation with V (100 microM) or CsA (5 microM) in Krebs-Henseleit buffer. Some slices were loaded with cholic acid (CA 5 microM) or tauro-ursodeoxycholic acid (T-UDCA 5 microM) to investigate the V and CsA effects under conditions of BA supplementation. BAs were determined in tissue and medium by HPLC with postcolumn derivatisation and fluorescence detection. V and CsA, influencing different targets in BA transport, enhanced slice concentrations of T- and glyco- (G-) conjugated CA only when exogenous CA was given additionally. This BA accumulation in tissue is more reflected at decreased medium concentrations of these BAs after V and CsA incubations. Both V and CsA also inhibited CA uptake into the slices. The acidic chenodeoxycholic acid (CDCA) synthesis pathway is disturbed T- and G-CDCA concentrations are diminished in slices and medium after V and CsA incubations. T-UDCA plus V or CsA enhanced not only its own slice concentration but also the concentration of the trihydroxylated tauro-muricholic acid (T-beta-MCA), reflecting the conversion of the accumulated dihydroxylated T-UDCA into the T-beta-MCA. The similar effects of V and CsA on BA transport and metabolism can be explained by mdr1 mediated disturbances of cellular ATP transport rather than by inhibition of individual BA transporters.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Tauroquenodesoxicólico
/
Verapamil
/
Ácidos Cólicos
/
Ciclosporina
/
Fígado
Limite:
Animals
Idioma:
En
Revista:
Exp Toxicol Pathol
Assunto da revista:
PATOLOGIA
/
TOXICOLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Alemanha