Effect of alpha-fetoprotein and indomethacin on arachidonic acid metabolism in P388D1 macrophages: role of leukotrienes.
Alpha-fetoprotein (AFP), is able to modify arachidonic acid metabolism in P388D1 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-PGF1 alpha 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-PGF1 alpha 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.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002460:Cell Line; D015232:Dinoprostone; D004347:Drug Interactions; D007213:Indomethacin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011458:Prostaglandins E / Q000096:biosynthesis; D051381:Rats; D013189:SRS-A / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis; D000509:alpha-Fetoproteins / Q000494:pharmacology*
D001095:Arachidonic Acids; D011458:Prostaglandins E; D013189:SRS-A; D000509:alpha-Fetoproteins; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin