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Cytochrome P450 Regulation and Drug Biotransformation During Inflammation and Infection

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The expression of cytochrome P450 and related biotransformation is altered during the operation of host defense mechanisms. This has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. In most cases individual cytochrome P450 forms are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA, protein and enzyme activity. The loss in drug metabolism is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors. Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation. When inflammatory responses are confined to the brain there is a loss of cytochrome P450 not only in the brain but also in peripheral tissues. This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source. In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component. This often results in altered drug responses and increased toxicities. Inflammation mediated alterations in the metabolism of endogenous compounds can lead to altered physiology. Changes in drug handling capacity during inflammation / infection will continue to be one of the many factors that complicate therapeutics.
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Keywords: cytochrome P450; drug biotransformation; inflammation; transcription factors

Document Type: Review Article

Affiliations: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7.

Publication date: June 1, 2004

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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