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Circadian time-dependent effects of experimental colitis on theophylline disposition and toxicity
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  • Yi Yang,
  • Pengcheng Wu,
  • Juntao Guo,
  • Zhixi Pan,
  • Shubin Lin,
  • Wanying Zeng,
  • Cunchuan Wang,
  • Zhiyong Dong,
  • Shuai Wang
Yi Yang
Jinan University First Affiliated Hospital
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Pengcheng Wu
Zhongshan Torch Development Zone People's Hospital
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Juntao Guo
Jinan University First Affiliated Hospital
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Zhixi Pan
Guangzhou University of Chinese Medicine
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Shubin Lin
Guangzhou University of Chinese Medicine
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Wanying Zeng
Guangzhou University of Chinese Medicine
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Cunchuan Wang
Jinan University First Affiliated Hospital
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Zhiyong Dong
Jinan University First Affiliated Hospital
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Shuai Wang
Guangzhou University of Chinese Medicine

Corresponding Author:[email protected]

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Abstract

Background and purpose: The impact of inflammatory bowel disease (IBD) on drug disposition is a critical concern, yet whether this impact is circadian time-dependent remains unexplored. We aim to discern the temporal effects of colitis on drug disposition and toxicity. Experimental Approach: The RNA-sequencing was used to screen colitis-affecting genes. The liver microsomal incubation and the pharmacokinetic study were used to analyze the enzymatic activity of key enzymes. Dual luciferase assays and chromatin immunoprecipitation (ChIP) were employed to elucidate regulatory relationships among molecules. Key Results: CYP1A2 and CYP2E1, pivotal in theophylline metabolism, exhibit reduced hepatic expression at Zeitgeber time (ZT)8 in colitis mice, a difference diminishing by ZT20. Moreover, theophylline metabolism is suppressed, and hepato-cardiac toxicities are markedly elevated in colitis mice at ZT8, while remaining unchanged at ZT20. The circadian clock component BMAL1 positively regulates CYP1A2 and CYP2E1 in the liver of colitis mice. A combination of assays, integrating liver-specific Bmal1 knockout mice and targeted activation of BMAL1 have unveiled that the dysregulation observed in Cyp1a2 and Cyp2e1 during colitis can be attributed to the perturbation in BMAL1 functionality in the liver. Luciferase reporter and ChIP assays collectively substantiate the role of BMAL1 in the modulation of Cyp1a2 and Cyp2e1 transcription through its binding affinity to E-box-like sites. Conclusion and implication: Our findings establish a strong link between IBD and chronopharmacology, shedding light on how IBD affects drug disposition and toxicity over time. Our research establishes a theoretical foundation for chronopharmacological approaches In the treatment of IBD.