Bibliographic Details
| Title: |
In silico and biological analyses of missense variants of the human biliary efflux transporter ABCC2: effects of novel rare missense variants. |
| Authors: |
Kölz, Charlotte, Gaugaz, Fabienne Z., Handin, Niklas, Schaeffeler, Elke, Tremmel, Roman, Winter, Stefan, Klein, Kathrin, Zanger, Ulrich M., Artursson, Per, Schwab, Matthias, Nies, Anne T. |
| Source: |
British Journal of Pharmacology; Nov2024, Vol. 181 Issue 22, p4593-4609, 17p |
| Subject Terms: |
MISSENSE mutation, GENETIC variation, MULTIDRUG resistance, DRUG therapy, XENOBIOTICS |
| Abstract: |
Background and Purpose: The ATP‐dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses. Experimental Approach: Targeted next‐generation sequencing of the ABCC2 gene was used to identify novel variants in European subjects (n = 143). Twenty‐six in silico tools were used to predict functional consequences. For biological validation, transport assays were carried out with membrane vesicles prepared from cell lines overexpressing the newly identified ABCC2 variants and estradiol β‐glucuronide and carboxydichlorofluorescein as the substrates. Key Results: Three novel rare ABCC2 missense variants were identified (W227R, K402T, V489F). Twenty‐five in silico tools predicted W227R as damaging and one as potentially damaging. Prediction of functional consequences was not possible for K402T and V489F and for the common linked variants V1188E/C1515Y. Characterisation in vitro showed increased function of W227R, V489F and V1188E/C1515Y for both substrates, whereas K402T function was only increased for carboxydichlorofluorescein. Conclusion and Implications: In silico tools were unable to accurately predict the substrate‐dependent increase in function of ABCC2 missense variants. In vitro biological studies are required to accurately determine functional activity to avoid misleading consequences for drug therapy. [ABSTRACT FROM AUTHOR] |
|
Copyright of British Journal of Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
