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Circadian time-dependent effects of experimental colitis on theophylline disposition and toxicity
Yi Yang1, Pengcheng Wu2, Juntao Guo3
1Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Background And Purpose:
Drug disposition undergoes significant alteration in patients with inflammatory bowel disease (IBD), yet circadian time-dependency of these changes remains largely unexplored. In this study, we aimed to determine the temporal effects of experimental colitis on drug disposition and toxicity.
Experimental Approach:
RNA-sequencing was used to screen genes relevant to colitis induced by dextran sodium sulfate in mice. Liver microsomes and pharmacokinetic analysis were used to analyze the activity of key enzymes. Dual luciferase assays and chromatin immunoprecipitation (ChIP) were employed to elucidate regulatory mechanisms.
Key Results:
RNA sequencing analysis revealed that colitis markedly influenced expression of cytochrome P450 (CYP) enzymes. Specifically, a substantial down-regulation of CYP1A2 and CYP2E1 was observed in livers of mice with colitis at Zeitgeber Time 8 (ZT8), with no significant changes detected at ZT20. At ZT8, the altered expression corresponded to diminished metabolism and enhanced incidence of hepato-cardiac toxicity of theophylline, a substrate specifically metabolized by these enzymes. A combination of assays, integrating liver-specific Bmal1 knockout and targeted activation of BMAL1 showed that dysregulation in CYP1A2 and CYP2E1 during colitis was attributable to perturbed BMAL1 functionality. Luciferase reporter and ChIP assays collectively substantiated the role of BMAL1 in regulating Cyp1a2 and Cyp2e1 transcription through its binding affinity to E-box-like sites.
Conclusion And Implication:
Our findings establish a strong link between colitis and chronopharmacology, shedding light on how IBD affects drug disposition and toxicity over time. This research provides a theoretical foundation for optimizing drug dosage in patients with IBD.
Insights
Inflammatory bowel disease (IBD) alters drug metabolism and toxicity in a time-dependent manner, linked to disrupted circadian rhythms and BMAL1 function. This impacts drug efficacy and safety in IBD patients.
Area of Science:
- Chronopharmacology
- Drug Metabolism
- Inflammatory Bowel Disease Research
Background:
- Drug disposition is significantly altered in patients with inflammatory bowel disease (IBD).
- The circadian time-dependency of these drug disposition changes in IBD remains largely unexplored.
- Experimental colitis models offer a platform to investigate temporal drug disposition alterations.
Purpose of the Study:
- To determine the temporal effects of experimental colitis on drug disposition.
- To investigate the impact of colitis on drug-induced toxicity over time.
- To elucidate the molecular mechanisms underlying time-dependent drug disposition changes in IBD.
Main Methods:
- RNA sequencing to identify colitis-affected genes in a mouse model.
- Liver microsome and pharmacokinetic analyses to assess enzyme activity.
- Dual luciferase assays and chromatin immunoprecipitation (ChIP) to explore regulatory pathways.
Main Results:
- Colitis significantly altered cytochrome P450 (CYP) enzyme expression, notably down-regulating CYP1A2 and CYP2E1 at Zeitgeber Time 8 (ZT8).
- This down-regulation correlated with reduced drug metabolism and increased toxicity of theophylline, a CYP1A2/CYP2E1 substrate, at ZT8.
- Perturbed BMAL1 (Brain and Muscle ARNT-Like 1) functionality was identified as the cause for dysregulated CYP1A2 and CYP2E1 expression, with BMAL1 directly regulating their transcription.
Conclusions:
- A strong link exists between colitis and chronopharmacology, demonstrating time-dependent effects of IBD on drug disposition and toxicity.
- Disrupted BMAL1 function due to colitis underlies the observed alterations in drug metabolism and toxicity.
- This research provides a foundation for optimizing drug dosage and timing in IBD patients.
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