Academic Journal
Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): Functional characterization and interindividual variability
| العنوان: | Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): Functional characterization and interindividual variability |
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| المؤلفون: | Ho, Richard H., Leake, Brenda F., Kilkenny, Dawn M., Schwabedissen, Henriette E.Meyer Zu, Glaeser, Hartmut, Kroetz, Deanna L., Kim, Richard B. |
| المصدر: | Paediatrics Publications |
| بيانات النشر: | Scholarship@Western |
| سنة النشر: | 2010 |
| المجموعة: | The University of Western Ontario: Scholarship@Western |
| مصطلحات موضوعية: | ABCB11, Bile acid, Bile salt export pump, Cholestasis, Pharmacogenetics, Polymorphism, Transporter |
| الوصف: | OBJECTIVES: Our aims were to identify and functionally characterize coding region nonsynonymous single nucleotide polymorphisms in the hepatic efflux transporter, bile salt export pump (BSEP; ABCB11), and to assess interindividual variability in BSEP expression. METHODS: We identified 24 single nucleotide polymorphisms, including nine nonsynonymous variants, in ABCB11 from genomic DNA of ∼250 ethnically diverse healthy individuals using denaturing high-performance liquid chromatography analysis and DNA sequencing. Wild type and variant BSEP were generated and functionally characterized for taurocholate transport activity in vitro in HeLa cells using a recombinant vaccinia-based method. BSEP expression was assessed by real-time mRNA analysis, western blot analysis, and immunofluorescence confocal microscopy. RESULTS: For the most part, polymorphisms were rare and ethnic-dependent. In vitro functional studies revealed several rare variants, including 616A>G, 1674G>C, 1772A>G, and 3556G>A, to be associated with significantly impaired taurocholate transport activity while the 890A>G variant trended towards impaired function but was not statistically significant. The 3556G>A variant was associated with reduced cell surface to total protein expression compared with wild-type BSEP. Expression of BSEP by mRNA and protein analysis was determined from a bank of human liver samples. Wide interindividual variability was noted in both mRNA (19-fold) and protein (31-fold) expression levels. The common variant 1331T>C was associated with significantly reduced hepatic BSEP mRNA levels. CONCLUSION: Accordingly, our study indicates there are functionally relevant polymorphisms in ABCB11 which may be of potential relevance in the predisposition to acquired liver disorders such as drug-induced cholestasis. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | https://ir.lib.uwo.ca/paedpub/2350; https://ir.lib.uwo.ca/context/paedpub/article/3358/viewcontent/nihms_202810.pdf |
| DOI: | 10.1097/FPC.0b013e3283349eb0 |
| الاتاحة: | https://ir.lib.uwo.ca/paedpub/2350 https://doi.org/10.1097/FPC.0b013e3283349eb0 https://ir.lib.uwo.ca/context/paedpub/article/3358/viewcontent/nihms_202810.pdf |
| رقم الانضمام: | edsbas.C0E79DDA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1097/FPC.0b013e3283349eb0 |
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