Knockout mouse

Gene expression

Nuclear receptor

Biology

Promoter

Gene

Endocrinology

Multidrug resistance-associated protein 2

Cell biology

Chromatin immunoprecipitation

Molecular biology

Transcription factor

Biochemistry

Pharmacology

Circadian rhythm

Pregnane X receptor

Transporter

Receptor

Chemistry

ATP-binding cassette transporter

Reporter gene

Theranostics

The intestinal exporter MRP2 plays an important role in disposition and elimination of a wide range of drugs.Here, we aimed to clarify the impact of circadian clock on intestinal MRP2, and to determine the molecular mechanisms for generation of diurnal MRP2 expression. Methods:The regulatory effects of Bmal1 on intestinal MRP2 expression were assessed using intestine-specific Bmal1 knockout (Bmal1 iKO ) mice and colon cancer cells.The relative mRNA and protein levels were determined by qPCR and Western blotting, respectively.Everted gut sac, cell viability and in situ intestinal perfusion experiments were performed to evaluate intestinal efflux of the MRP2 substrate methotrexate (MTX).Toxicity and pharmacokinetic experiments were performed with Bmal1 iKO mice and control littermates (Bmal1 fl/fl mice) after oral gavage of MTX.Transcriptional gene regulation was investigated using luciferase reporter, mobility shift and chromatin immunoprecipitation (ChIP) assays.Results: Bmal1 iKO mice were generated by inter...

The Circadian Clock Gene <i>Bmal1</i> Controls Intestinal Exporter MRP2 and Drug Disposition

The Circadian Clock Gene Bmal1 Controls Intestinal Exporter MRP2 and Drug Disposition