Circadian Clock Is Involved in Regulation of Hepatobiliary Transport Mediated by Multidrug Resistance-Associated Protein 2

Oh, Ju‐Hee; Lee, Juhyun; Han, Dong Hee; Cho, Sehyung; Lee, Young Joo

doi:10.1016/j.xphs.2017.04.071

Cited by 28 publications

(17 citation statements)

References 42 publications

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“…MRP2 is an important MRP protein best known for its apical membrane location in enterocytes and hepatocytes 19. This unique location supports its critical roles in intestinal defense against xenobiotic threats and in biliary drug elimination 20,21.…”

Section: Introductionmentioning

confidence: 85%

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

Yu¹,

Zhang²,

Zhou³

et al. 2019

Theranostics

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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-crossing the mice carrying a Bmal1 exon 8 floxed allele ( Bmal1 fl/fl ) with Villin-Cre mice. Intestinal MRP2 expression exhibited a diurnal oscillation in Bmal1 fl/fl mice with a zenith value at ZT6. Bmal1 ablation caused reductions in Mrp2 mRNA and protein levels [as well as in transport activity (measured by MTX)], and blunted their diurnal rhythms. Intestinal ablation of Bmal1 abrogated circadian time-dependency of MTX pharmacokinetics and toxicity. Bmal1/BMAL1 regulation of rhythmic Mrp2/MRP2 expression was also confirmed in the colon cancer CT26 and Caco-2 cells. Based on a combination of luciferase reporter, mobility shift and ChIP assays, we found that Dbp activated and E4bp4 repressed Mrp2 transcription via specific binding to a same D-box (-100/-89 bp) element in promoter region. Further, Bmal1 directly activated the transcription of Dbp and Rev-erbα through the E-boxes, whereas it negatively regulated E4bp4 via the transcriptional repressor Rev-erbα. Positive regulation of Mrp2 by Rev-erbα was also observed, and attained through modulation of E4bp4. Conclusion : Bmal1 coordinates temporal expressions of DBP (a MRP2 activator), REV-ERBα (an E4BP4 repressor) and E4BP4 (a MRP2 repressor), generating diurnal MRP2 expression.

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Section: Introductionmentioning

confidence: 85%

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

Yu¹,

Zhang²,

Zhou³

et al. 2019

Theranostics

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“…2). This is not surprising because knockout of single core clock gene (e.g., Clock, Bmal1, Per2 and Rev-erbα) cannot completely abolish the rhythms of all circadian genes, but usually caused disruptions to circadian rhythms to a certain degree 43,44 . It is reasoned that circadian clock is a complicated system whose functions cannot be determined by only one of its components.…”

Section: Discussionmentioning

confidence: 99%

Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

et al. 2019

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Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.

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“…In fact, the biliary clearance and cumulative excretion of phenolsulfonphthalein, an MRP2 substrate, was highest at ZT 12, that is, approximately 8 hr after the mRNA peak (Figure 2). Nevertheless, P‐gp and BCRP protein expression did not demonstrate a significant rhythm in the same study, despite a 24‐hr transcriptional oscillation of Abcb1 (Oh, Lee, Han, Cho, & Lee, 2017) and Abcg2 (exon 1B isoform; Hamdan et al, 2012). In the liver from cynomolgus monkeys, P‐gp, BCRP, MRP2, and CYP3A protein levels did not reveal significant circadian variations.…”

Section: Chronopharmacokinetics: Non‐clinical Datamentioning

confidence: 74%

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

Bicker

Alves

Falcão

2020

British J Pharmacology

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The importance of drug dosing time in pharmacokinetics, pharmacodynamics, and toxicity is receiving increasing attention from the scientific community. In spite of mounting evidence that circadian oscillations affect drug absorption, distribution, metabolism, and excretion (ADME), there remain many unanswered questions in this field and, occasionally, conflicting experimental results. Such data arise not only from translational difficulties caused by interspecies differences but also from variability in study design and a lack of understanding of how the circadian clock affects physiological factors that strongly influence ADME, namely, the expression and activity of drug transporters. Hence, the main goal of this review is to provide an updated analysis of the role of the circadian rhythm in drug absorption, distribution across bloodtissue barriers, metabolism in hepatic and extra-hepatic tissues, and hepatobiliary and renal excretion. It is expected that the research suggestions proposed here will contribute to a tissue-targeted and time-targeted pharmacotherapy.

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Circadian Clock Is Involved in Regulation of Hepatobiliary Transport Mediated by Multidrug Resistance-Associated Protein 2

Cited by 28 publications

References 42 publications

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

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

Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

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