Cytochrome P450 pathways of arachidonic acid metabolism

Abstract

Cytochrome P450s metabolize arachidonic acid to hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. These eicosanoids are formed in a tissue and cell-specific manner and have numerous biological functions. Of major interest are the opposing actions of hydroxyeicosatetraenoic and epoxyeicosatrienoic acids within the vasculature. Regio- and stereoisomeric epoxyeicosatrienoic acids have potent vasodilatory properties while 20-hydroxyeicosatetraenoic acid is a potent vasoconstrictor. Both effects are mediated through actions on large-conductance Ca2+-activated K+ channels. Cytochrome P450-derived eicosanoids are also important in the regulation of ion transport, and have recently been shown to influence a number of fundamental biological processes including cellular proliferation, apoptosis, inflammation, and hemostasis. The formation of these functionally relevant eicosanoids is tightly controlled by the expression and activity of the cytochrome P450 epoxygenases and hydroxylases. In addition, soluble epoxide hydrolase catalyzes the hydrolysis of epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids, and the activity of this enzyme is a critical determinant of tissue epoxyeicosatrienoic and dihydroxyeicosatrienoic acid levels. The intracellular balance between epoxyeicosatrienoic, dihydroxyeicosatrienoic and hydroxyeicosatetraenoic acids influences the biological response to these eicosanoids and alterations in their levels have recently been associated with certain pathological conditions. The involvement of the cytochrome P450-derived eicosanoids in a wide array of biological functions and the observation that levels are altered in pathological conditions suggest that the enzymes involved in the formation and degradation of these fatty acids may be novel therapeutic targets.