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

Yu, Fangjun; Zhang, Tianpeng; Zhou, Cui; Xu, Haiman; Guo, Lianxia; Chen, Min; Wu, Baojian

doi:10.7150/thno.33395

Cited by 65 publications

(52 citation statements)

References 48 publications

(57 reference statements)

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“…In addition to gender, microbiome may be another influencing factor to inter-subject variations of circadian pattern in Cyp3a11 40 . We show Bmal1 controls circadian expressions of Cyp3a11 in the present study and of intestinal Mrp2 in our recent study 41 . BMAL1 has potential to regulate other key metabolic enzymes and transporters such as UGT1A1, CES2 and P-gp 42 .…”

Section: Discussionsupporting

confidence: 80%

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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Section: Discussionsupporting

confidence: 80%

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

et al. 2019

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“…Diurnal expression of some types of ABC transporters are regulated by the molecular circadian clock 10 , 11 , 13 . Gene products of Clock and Bmal1 form a heterodimer that activates the transcription of Period ( Per ) and Cryptochrome ( Cry ) genes through E-box (CACGTG) or E-box-like (CACGTT) enhancer sequences 42 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several types of ABC transporters also function in the biliary, intestinal, and renal elimination of drugs 9 . The expression and function of some ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer-resistant protein (BCRP), exhibit diurnal variation, resulting in dosing time-dependent differences in drug disposition 10 – 13 .…”

Section: Introductionmentioning

confidence: 99%

Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

Kato

Tsurudome

Kanemitsu

et al. 2020

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the expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistanceassociated protein-4 (MRP4), an ATP binding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHPinduced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity. Daily variations in biological functions, such as gene expression and protein synthesis, are thought to be important factors affecting the efficacy and/or toxicity of drugs; a large number of drugs cannot be expected to have the same potency at different administration times 1,2. Consequently, administration of drugs at appropriate times of day can improve the outcome of pharmacotherapy by maximizing their potency and minimizing their toxicity, whereas drug administration at an inappropriate time of day can induce severe side effects. Dosing time-dependent differences in the drug effects are due, at least in part, to 24-h changes in drug disposition such as absorption, distribution, metabolism, and elimination 3-6. ATP binding cassette (ABC) transporters are widely known as energy-dependent efflux pumps that expel cytotoxic substances, including chemotherapeutic drugs. They are expressed in epithelial cells of several organs, including the brain, liver, intestine, and kidney 7 , and function as a barrier to limit intestinal absorption of many drugs and their distribution to different tissues 8. Furthermore, several types of ABC transporters also function in the biliary, intestinal, and renal elimination of drugs 9. The expression and function of some ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer-resistant protein (BCRP), exhibit diurnal variation, resulting in dosing time-dependent differences i...

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“…In this study, we found that molecular components of the circadian clock can regulate the time‐dependent expression of the Gp2 gene, a key regulator in intestinal immunity, in mouse Peyer's patches through the activation of CREB. Previous studies demonstrated circadian expression of intestinal cell‐surface proteins, such as xenobiotic efflux transporter (e.g., Mdr1, Bcrp and Mrp2), and their expression rhythm was also controlled by a molecular clock (Hamdan et al, 2012; Murakami, Higashi, Matsunaga, Koyanagi, & Ohdo, 2008; Yu et al, 2019). The expression of some such transporters increases from the late light phase to the early dark phase, during which nocturnal active rodents wake up and start daily food intake.…”

Section: Discussionmentioning

confidence: 99%

Circadian expression of Glycoprotein 2 (Gp2) gene is controlled by a molecular clock in mouse Peyer's patches

et al. 2020

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The expression levels of many cell‐surface proteins vary with the time of day. Glycoprotein 2 (Gp2), specifically expressed on the apical surface of M cells in Peyer's patches, functions as a transcytotic receptor for mucosal antigens. We report that cAMP response element‐binding protein (CREB) regulates the transcription of the Gp2 gene, thereby generating the circadian change in its expression in mouse Peyer's patches. The transcytotic receptor activity of Gp2 was increased during the dark phase when the Gp2 protein abundance increased. Rhythmic expression of clock gene mRNA was observed in mouse Peyer's patches, and expression levels of Gp2 mRNA also exhibited circadian oscillation, with peak levels during the early dark phase. The promoter region of the mouse Gp2 gene contains several cAMP response elements (CREs). Chromatin immunoprecipitation assays revealed that CREB bound to the CREs in the Gp2 gene in Peyer's patches. Forskolin, which promotes CREB phosphorylation, increased the transcription of the Gp2 gene in Peyer's patches. As phosphorylation of CREB protein was increased when Gp2 gene transcription was activated, CREB may regulate the rhythmic expression of Gp2 mRNA in Peyer's patches. These findings suggest that intestinal immunity is controlled by the circadian clock system.

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

Cited by 65 publications

References 48 publications

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

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

Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

Circadian expression of Glycoprotein 2 (Gp2) gene is controlled by a molecular clock in mouse Peyer's patches

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