Biological Relevance of the 12-Lipoxygenase Pathway for Platelet and Lymphocyte Functions

Abstract

The 12-lipoxygenase activity has been the first animal lipoxygenase activity reported; it was discovered during the study of the oxygenation of arachidonic acid by blood platelets (1,2). It produces 12(S)-hydroperoxy-eicosa-5Z,8Z,10E,14Z-tetraenoic acid (12-HpETE) which is efficiently reduced into the corresponding alcohol derivative (12-HETE) by a cytosolic glutathione-dependent peroxidase (3) (Figure 1). In platelets, 12-lipoxy-genase has been mainly located in the cytosol, but also exists as a membrane-associated form (4). 12-HpETE may also be transformed into hydroxy-epoxy-eicosatrienoic derivatives, the hepoxilins, that are in turn further hydrolyzed into trihydroxy products, the triox-ilins (5–8). The n-8 oxygenation of arachidonic acid and of several other eicosapolyenoic acids by the 12-lipoxygenase appears less regiospecific for docosapolyenoic acids of the n-3 family. Indeed two products, namely 11- and 14-hydroxy derivatives from docosa-hexaenoic (22:6n-3) and docosapentaenoic (22:5n-3) acids, have been characterized by using intact platelets (9,10), whereas only the 14-hydroxy derivative was obtained from the 22:5n-6 isomer (10). Another difference in terms of fatty acid-specificity of 12-lipoxy-genase deals with the relative efficacy of their conversion into monohydroxy derivatives. As a matter of fact, the two positional isomers of eicosatrienoic acid, 20:3n-6 and 20:3n-9, are fairly good substrates of the 12-lipoxygenase (11,12), attaining levels of conversion close to that of arachidonic acid, but the 12-lipoxygenation of 20:5n-3 is much lower (11,13). The latter requires additional hydroperoxides such as 12-HpETE from arachidonic acid (14,15).