HYPOXIA AND THE TRANSCRIPTIONAL REGULATION OF CYP GENES IN CELLS

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Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and activator protein-1 (or AP-1). We have identified a novel target gene that is activated in hypoxia. This gene produces an enzyme, termed cytochrome P450 2J2, that acts on fatty acids which are present in cell membranes and converts them into molecules that control the flow of potassium and calcium ions into cells. Alterations in the flow of such ions into cells have been observed previously in hypoxia but the mechanism of this effect is unclear. Thus, cytochrome P450 2J2 is switched on in hypoxia and generates fatty acid metabolites that control protective ion fluxes in cells.