Rare Variants in the ABCG2 Promoter Modulate In Vivo Activity

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Rachel J EclovDeanna L Kroetz

Abstract

ABCG2 encodes the breast cancer resistance protein (BCRP), an efflux membrane transporter important in the 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 activities of reference and variant ABCG2 sequences were compared in human hepatocellular carcinoma cell (HepG2), human embryonic kidney cell (HEK293T), human colorectal carcinoma cell (HCT116), and human breast adenocarcinoma cell (MCF-7) 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 was also examined in vivo using the hydrodynamic tail vein assay, and two single nucleotide polymorphisms (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, whereas the rs76656413 probe had a shift in transcription factor bi...Continue Reading

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Citations

Apr 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qingcheng MaoJoanne Wang
May 11, 2021·Frontiers in Oncology·Amrutha MohanTessy Thomas Maliekal
Sep 30, 2021·Cellular and Molecular Life Sciences : CMLS·Samiksha KukalRitushree Kukreti

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