RT Journal Article
SR Electronic
T1 Rare Variants in the ABCG2 Promoter Modulate In Vivo Activity
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.079541
DO 10.1124/dmd.117.079541
A1 Rachel J Eclov
A1 Mee J. Kim
A1 Robin P. Smith
A1 Nadav Ahituv
A1 Deanna L. Kroetz
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/02/21/dmd.117.079541.abstract
AB ABCG2 encodes the breast cancer resistance protein (BCRP), an efflux membrane transporter important in detoxification of xenobiotics. In the present study, the basal activity of the ABCG2 promoter in liver, kidney, intestine and breast cell lines was examined using luciferase reporter assays. The promoter activity of reference and variant ABCG2 sequences were compared in HepG2, HEK293T, HCT116 and MCF-7 cell lines. The ABCG2 promoter activity was strongest in the kidney and intestine cell lines. Four variants in the basal ABCG2 promoter (rs76656413, rs66664036, rs139256004 and rs59370292) decreased the promoter activity by 25-50% in at least three of the four cell lines. The activity of these four variants were also examined in vivo using the hydrodynamic tail vein assay, and two SNPs (rs76656413 and rs59370292) significantly decreased in vivo liver promoter activity by 50-80%. Electrophoretic mobility shift assays confirmed a reduction in nuclear protein binding to the rs59370292 variant probe, while the rs76656413 probe had a shift in transcription factor binding specificity. While both rs59370292 and rs76656413 are rare variants in all populations, they could contribute to patient-level variation in ABCG2 expression in the kidney, liver and intestine.