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http://purl.uniprot.org/citations/17264802http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17264802http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17264802http://www.w3.org/2000/01/rdf-schema#comment"

Objectives

Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms.

Methods

ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay.

Results

Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional.

Conclusion

In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.org/dc/terms/identifier"doi:10.1097/01.fpc.0000230418.28091.76"xsd:string
http://purl.uniprot.org/citations/17264802http://purl.org/dc/terms/identifier"doi:10.1097/01.fpc.0000230418.28091.76"xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Lang C."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Lang C."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Beuers U."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Beuers U."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Kerb R."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Kerb R."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Kullak-Ublick G.A."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Kullak-Ublick G.A."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Lang T."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Lang T."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Meier P.J."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Meier P.J."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Meier Y."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Meier Y."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Pauli-Magnus C."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Pauli-Magnus C."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Stieger B."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/author"Stieger B."xsd:string
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/date"2007"xsd:gYear
http://purl.uniprot.org/citations/17264802http://purl.uniprot.org/core/date"2007"xsd:gYear
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