Cytochrome P450 epoxygenases and
hydroxylases play a regulatory role in the activation and suppression of
inflammation by generating or metabolizing bioactive mediators.
CYP2C and CYP2J epoxygenases convert
arachidonic acid to anti-inflammatory epoxyeicosatrienoic
acids, which have protective effects in a variety of disorders including
cardiovascular disease and
metabolic syndrome.
CYP4A and CYP4F
hydroxylases have the ability to metabolize multiple substrates related to the regulation of
inflammation and
lipid homeostasis, and it is a challenge to determine which substrates are physiologically relevant for each
enzyme; the best-characterized activities include generation of
20-hydroxyeicosatetraenoic acid and inactivation of
leukotriene B4. The expression of hepatic
drug-metabolizing
cytochrome P450s is modulated by
cytokines during
inflammation, resulting in changes to the pharmacokinetics of prescribed medications.
Cytochrome P450s are therefore the focus of intersecting challenges in the pharmacology of
inflammation: not only do they represent targets for development of new anti-inflammatory drugs but they also contribute to variability in
drug efficacy or toxicity in inflammatory disease. Animal models and primary hepatocytes have been used extensively to study the effects of
cytokines on
cytochrome P450 expression and activity. However, it is difficult to predict changes in
drug exposure in patients because the response to
inflammation varies depending on the disease state, its time course, and the
cytochrome P450 involved. In these circumstances, the development of endogenous markers of
cytochrome P450 metabolism might provide a useful tool to reevaluate
drug dosage and choice of
therapy.