Revised Manuscript Received April 30, 1993 abstract: Lipoxins are tetraene-containing eicosanoids that possess biological activity in several organ systems. To determine their route of furthermetabolism,[11, 12-3H] lipoxin A4 was prepared and incubated with human neutrophils, promyelocytic leukemia (HL-60) cells, and adherent monocytes. Intact neutrophils and undifferentiated HL-60 cells did not significantly metabolize [11, 12-3H] LXA4, while HL-60 cells differentiated withPMA to monocyte/macrophage lineage rapidly (< 15 s) transformed this eicosanoid. The major radiolabeled LXA4-derived metabolites were characterized by physical methods and were shown to be 15-OXO-LXA4, 13, 14-dihydro-15-oxo-LXA4, and 13, 14-dihydro-LXA4. Substrate competition with cell-free supernatants from differentiated HL-60 cells suggests that lipoxins compete for 15-hydroxypros-taglandin dehydrogenase activity or an equivalent enzyme system. In addition, adherent monocytes exposed to [11, 12-3* H] LXA4 rapidly metabolized (> 60% within 30 s) the label to its oxo and dihydro derivatives. These results indicate that, unlike leukotrienes, LXA4 is subject to dehydrogenation and reduction of its conjugated tetraene to form triene-containing products. Moreover, they suggest that monocytes participate in lipoxin metabolism in their local milieu.