Effect of alpha-fetoprotrein and indomethacin on arachidonic acid metabolism in P388D1 macrophages : Role of leuxotrienes

Alpha-fetoprotein (AFP),is able to modify arachidonic acid metabolism In P388DI macrophage - like cells. AFP has been shown to induce mobilization of arachidonic acid and consequently an enhanced production of leukotrienes.The action of AFP on the cyclooxygenase pathway appears, however, more complex, as this protein simultaneously decreases the total amount of cyclooxygenase products and raises the production of PGE2, 6-keto-PGF1α and to a lesser extent of thromboxane B2. On the other hand, indomethacin abolishes the synthesis of PGE2 but has no effect on 6-keto-PGFlα and thromboxane B2. Indomethacin used in combination with AFP partly loses its inhibiting effect on PGE2 synthesis and paradoxically leads to a “superactivation” of P388D1 cells demonstrated by a very high arachidonic acid mobilization, an enhancement of both leukotriene synthesis and cyclooxygenase activity. Evidence for a binding of indomethacin to AFP was obtained that partly explains these results. In addition, it is shown that the effects of AFP and AFP+Indomethacin on cyclooxygenase activity might be explained by the endogenous synthesis of leukotrienes.