Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function.
Pharmacogenomics J
; 11(1): 25-34, 2011 Feb.
Article
en En
| MEDLINE
| ID: mdl-20351751
ABSTRACT
ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants -24C>T, 1249G>A and 3972C>T are leading to inter-individual differences of bioavailability of various endogenous and exogenous compounds. Considering ABCC2 haplotypes, we investigated DNA-protein binding properties, mRNA secondary structure, mRNA stability, protein expression and transport activity in various cell lines and analyzed the bioavailability of talinolol in 24 healthy Caucasian volunteers; -24C>T had no clear influence on DNA-protein binding and the mRNA stability did not differ significantly. In transfected HEK293T/17 cells, haplotypes H9 (CGT), H10 (TGC) and H12 (TGT) had significantly lower protein expression, whereas H2 (CAC) exhibited significantly increased protein expression compared to the wild type (H1, CGC) 32.7 ± 8.8, 73.1 ± 6.3; 44.0 ± 15.5 and 115.2 ± 8.2%, respectively. This corresponded with efflux rates of the fluorescent dye glutathione-methylfluorescein in vitro and by trend with talinolol bioavailability in vivo. In conclusion our results show a haplotype-dependent influence on transport capacity of ABCC2, which seems to be mainly based on posttranscriptional modification of protein expression rather than transport rates.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
/
ARN Mensajero
/
Procesamiento Postranscripcional del ARN
/
Regulación de la Expresión Génica
/
Proteínas Asociadas a Resistencia a Múltiples Medicamentos
Límite:
Adult
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Pharmacogenomics J
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Alemania