Functional defect caused by the 4544G>A SNP in ABCC2 : potential impact for drug cellular disposition.

Elens, Laure [UCL] Tyteca, Donatienne [UCL] Panin, Nadtha [UCL] Courtoy, Pierre J. [UCL] Lison, Dominique [UCL] Demoulin, Jean-Baptiste [UCL] Haufroid, Vincent [UCL]

ABCC2 contributes to the active cellular efflux of several endogenous and exogenous compounds. The 4544G>A (rs8187710) single nucleotide polymorphism (SNP), which is coding for a C1515Y substitution, has been previously associated with susceptibility to cholestatic liver disease, doxorubicin cardiotoxicity, nonalcoholic fatty liver disease, decreased graft function after renal transplantation and tenofovir-induced proximal nephropathy. It is also involved in differential flavopiridol disposition and increased lopinavir (LPV) cellular accumulation in vivo. The aim of the present study was to investigate whether the 4544G>A SNP causes alterations in ABCC2-mediated transport towards different substrates and to explore the underlying molecular mechanisms.