Lipoxygenase Gene Disruption Studies

Abstract

Mammalian lipoxygenase enzymes (Figure 1) are derived from a multi-gene family, each member consisting of 14 exons (1,2). The 5-lipoxygenase gene is distinct from other lipoxygenase genes in its large size and its location on a separate chromosome (10q1 1.2 in humans and central chromosome 6 in mice) (1-5). A cluster of lipoxygenase genes located on mouse chromosome 11 (5,6) contains genes that encode three distinct 12(S)-lipoxy-genases, referred to as “platelet-type,” “leukocyte-type” and “epidermal-type” (1,7,8). Although substantial information is known about the ability of the various lipoxygenases to oxygenate arachidonic acid at a specific carbon atom position, relatively little is understood regarding the physiological roles of the various metabolites such as 12-hy-dro(pero)xy-eicosatetraenoic acid (12-H(p)ETE) and 15-H(p)ETE. Diverse biological activities have been assigned to lipoxygenase-derived eicosanoids and pathophysiological elevations in their synthesis have been reported (9-11). However, it remains to be determined how relevant these findings are to physiological models in vivo. Thus, we undertook the approach of targeted lipoxygenase gene disruption to elucidate possible functions associated with the various eicosanoid metabolites generated from these pathways. In this review, an effort will be made to emphasize the current status of experimental results using 5-lipoxygenase and 12-lipoxygenase-deficient mice and potential future applications in disease models and other physiological studies.