Renal Cytochrome P450-Dependent Eicosanoids

Abstract

Several of the arachidonic acid (AA) products generated by cytochrome P450 monooxygenases have prominent direct effects on vasomotion and ion transport (1). Unlike cyclooxygenases and lipoxygenases, which are dioxygenases and have narrow substrate specificity, P450 oxygenases are monooxygenases and are capable of metabolizing a range of substrates (2). They have absolute requirements for NADPH/NADH and a flavoprotein, either a reductase and/or cytochrome b₅. Synthesis of P450-AA metabolites can be characterized according to the arachidonate metabolite (Figure 1)— epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) — generated by a score of more than 200 isoforms that are encoded by the cytochrome P450 gene superfamily. These oxygenases metabolize drugs, xenobiotics, vitamins, steroids and fatty acids, including AA. Further, unlike prostanoids, EETs and HETEs can be esterified to the Sn-2 position of phospholipids from which storage site they can be released as mediators (3), presumably to participate in transmembrane signaling. While esterified to membrane phospholipids, they may influence the physiochemical properties of cells such as permeability. The wide distribution of the P450 system and the diverse activities of P450-AA metabolites on blood vessels and transporting epithelia make them prime candidates for participation in the regulation of the circulation (4).