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Functional characterization of common protein variants in the efflux transporter ABCC11 and identification of T546M as functionally damaging variant

Abstract:

Multidrug resistance protein 8 (ABCC11) is an efflux transporter for anionic lipophilic compounds, conferring resistance to antiviral and anticancer agents like 5-fluorouracil (5-FU). ABCC11 missense variants may contribute to variability in drug response but functional consequences, except for the 'earwax variant' c.538G>A, are unknown. Using the 'Screen and Insert' technology, we generated human embryonic kidney 293 cells stably expressing ABCC11 missense variants frequently occurring in different ethnic populations: c.57G>A, c.538G>A, c.950C>A, c.1637C>T, c.1942G>A, c.4032A>G. A series of in silico prediction analyses and in vitro plasma membrane vesicle uptake, immunoblotting and immunolocalization experiments were undertaken to investigate functional consequences. We identified c.1637C>T (T546M), previously associated with 5-FU-related toxicity, as a novel functionally damaging ABCC11 variant exhibiting markedly reduced transport function of 5-FdUMP, the active cytotoxic metabolite of 5-FU. Detailed analysis of 14 subpopulations revealed highest allele frequencies of c.1637C>T in Europeans and Americans (up to 11%) compared with Africans and Asians (up to 3%).The Pharmacogenomics Journal advance online publication, 21 April 2015; doi:10.1038/tpj.2015.27.

PubMed ID: 25896536

Projects: G2: Clinical Translation to Non-Invasive Volunteer Setting, G3: Clinical Translation to Pharmaceutical Drug Development

Journal: Pharmacogenomics J
Citation: Pharmacogenomics J. 2015 Apr 21. doi: 10.1038/tpj.2015.27.
Date Published: 22nd Apr 2015

Authors: R. Arlanov, T. Lang, G. Jedlitschky, E. Schaeffeler, T. Ishikawa, M. Schwab, A. T. Nies

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