Role of Cytochrome P450s in Inflammation

Abstract

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.

Introduction

Some cytochrome P450s (CYPs) play an active role in inflammation by converting fatty acids to pro- or anti-inflammatory mediators. Most focus has been on the products of arachidonic acid (eicosatetraenoic acid), a 20-carbon ω-6 polyunsaturated fatty acid (PUFA), but there is growing interest in the metabolism of other PUFAs, including ω-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The role of CYPs in arachidonic acid metabolism is summarized in Fig. 1. CYP epoxygenases convert arachidonic acid to anti-inflammatory epoxyeicosatrienoic acids (EETs) and include enzymes in the CYP2C and CYP2J families. CYP hydroxylases convert arachidonic acid to proinflammatory 20-hydroxyeicosatetraenoic acid (20-HETE) and include enzymes in the CYP4A and CYP4F families. Therefore, CYPs can participate in the suppression, activation, and resolution of inflammation. CYPs are often described as the third arm of arachidonic acid metabolism; the other two arms are the cyclooxygenase (COX) pathway that produces prostanoids such as prostaglandins (PGs), and the lipoxygenase (LOX) pathway that produces leukotrienes (LTs) and a variety of HETEs. CYPs can inactivate or modify products of these other pathways, and this adds to the complexity of regulatory networks. CYP activity is determined mainly by the availability of substrate: inflammatory cytokines or other signals stimulate release of arachidonic acid from cell membranes by phospholipases, and the products of arachidonic acid (eicosanoids) then depend on which CYP enzymes are expressed in a particular cell type. However, CYP expression levels can change during inflammation and disease progression, and this adds another dynamic to the regulation of inflammation that is poorly understood. In addition, the expression of hepatic drug-metabolizing CYPs is modified during inflammation, resulting in changes in the clearance of drugs. This was originally considered to be a nonspecific downregulation of CYP expression, as the liver diverts its resources to the production of acute phase proteins. However, detailed analysis of animal models and primary hepatocytes has shown that individual CYPs are regulated by inflammatory cytokines in diverse ways. The consequences for drug pharmacokinetics are difficult to predict and depend on the disease context and the particular CYP involved. These issues are relevant to classic inflammatory responses to injury and infection and also to chronic inflammatory diseases such as arthritis, cardiovascular disease, and cancer.