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Decrease in brain cytochrome P450 enzyme activities during infection and inflammation of the central nervous system.

M Monshouwer1, D Agnello, P Ghezzi

  • 1Department of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. mario.monshouwer@eu.pnu.com

Neuroimmunomodulation
|December 22, 2000
PubMed
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Central nervous system (CNS) infection and inflammation, marked by elevated tumor necrosis factor (TNF), significantly reduce cytochrome P450 metabolism in both the brain and liver.

Area of Science:

  • Neuroimmunology
  • Pharmacology
  • Toxicology

Background:

  • Central nervous system (CNS) infections and inflammation can impact drug metabolism.
  • Cytochrome P450 enzymes are crucial for metabolizing xenobiotics, including drugs, in the brain and liver.
  • Tumor necrosis factor (TNF) is a key inflammatory cytokine implicated in various neurological conditions.

Purpose of the Study:

  • To investigate the effect of CNS infection and inflammation on cytochrome P450-dependent activities.
  • To compare the impact of lipopolysaccharide (LPS) and experimental autoimmune encephalomyelitis (EAE) models on P450 metabolism.
  • To determine the role of TNF in modulating P450 activity during CNS inflammation.

Main Methods:

  • Utilized two models: intracerebroventricularly injected lipopolysaccharide (LPS) and experimental autoimmune encephalomyelitis (EAE).

Related Experiment Videos

  • Assessed cytochrome P450-dependent activities, including aminopyrine N-demethylase (AMND) and ethoxycoumarin O-deethylase (ECOD), in brain, spinal cord, and liver microsomes.
  • Measured levels of tumor necrosis factor (TNF) in brain, spinal cord, and serum.

    • Main Results:

    • In the LPS model, brain microsome AMND and ethoxycoumarin O-deethylase (ECOD) activities decreased by 35% and 20%, respectively.
    • In the EAE model, only ECOD activity was significantly reduced (18%) in brain microsomes.
    • Liver P450, AMND, and ECOD activities decreased only in the LPS model. TNF was elevated in brain and spinal cord tissues in both models.

    Conclusions:

    • CNS infection or inflammation, associated with elevated TNF, impairs P450-dependent metabolism in the brain.
    • This impairment extends to liver metabolism, particularly in the LPS model.
    • Findings highlight the significant impact of neuroinflammation on drug metabolism pathways.