Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition

Area of Science:

• Pharmacology
• Gastroenterology
• Biochemistry

Background:

• Systemic exposure of metronidazole increases in inflammatory bowel diseases (IBDs).
• The underlying mechanisms for this altered drug disposition remain unknown.
• Experimental colitis models are crucial for studying IBD-related pharmacokinetic changes.

Purpose of the Study:

• To elucidate the mechanisms by which experimental colitis affects metronidazole disposition in mice.
• To identify the specific enzymes and signaling pathways involved in altered metronidazole metabolism during colitis.

Main Methods:

• Dextran sulfate sodium (DSS)-induced experimental colitis model in mice.
• Hepatic microsomal incubation to assess metronidazole hydroxylation.
• Quantitative analysis of CYP2A5 expression and NF-κB activation.
• Luciferase reporter and chromatin immunoprecipitation assays to study gene regulation.

Main Results:

• Metronidazole systemic exposure and 2-hydroxymetronidazole production were elevated and inhibited, respectively, in colitis mice.
• CYP2A5, the enzyme catalyzing metronidazole hydroxylation, was downregulated in the liver during colitis.
• Activated hepatic NF-κB directly downregulated Cyp2a5 transcription by binding to its promoter.
• CYP2A5 downregulation was disease-dependent, observed in spontaneous colitis models and correlated with colitis severity.

Conclusions:

• Activated hepatic NF-κB in experimental colitis downregulates CYP2A5 expression.
• This downregulation of CYP2A5 leads to altered metronidazole disposition in IBD.
• Findings provide a mechanistic basis for pharmacokinetic instability in IBD and inform rational drug use.