METABOLISM OF 6-TRANS-ISOMERS OF LEUKOTRIENE B-4 IN CULTURED HEPATOMA-CELLS AND IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES - IDENTIFICATION OF ADELTA(6)-REDUCTASE METABOLIC PATHWAY

The intermediate metabolic events which degrade hydroxy polyunsaturate d fatty acids is largely unknown. Such molecules are common products o f lipid peroxidation and lipoxygenase catalyzed oxidation of arachidon ic acid, Metabolism of two 5,12-dihydroxyeicosatetraenoic acids, 6-tra ns-LTB(4) (leukotriene B-4), and 6-trans-12-epi-LTB(4) was studied in HepG2 cells (a human-derived hepatoma cell line). Extensive metabolism was observed with a major metabolite identified as 4-hydroxy-6-dodece noic acid for both epimers. Incubation of 6-trans-LTB(4) epimers at sh orter times revealed the formation of intermediate metabolites, includ ing 6-hydroxy-4,8-tetradecadienoic acid and 8-hydroxy-4,6,10-hexadecat rienoic acid suggesting beta-oxidation as the major pathway leading to the formation of the common terminal metabolite. Two additional metab olites were structurally elucidated as 5-oxo-6,7-dihydro-LTB(4) and 6, 7-dihydro-LTB(4) which have not been previously described. Formation o f 5-oxo-6,7-dihydro-LTB(4) and 6,7-dihydro-LTB(4) were also observed d uring metabolism of 6-trans-12-epi-LTB(4) in human polymorphonuclear l eukocytes. Of particular interest is the metabolism of these compounds by beta-oxidation from the carboxyl terminus, a process which is not observed with leukotriene B-4 or leukotriene C-4. Identification of th ese metabolites suggested the operation of the 5-hydroxyeicosanoid deh ydrogenase pathway followed by a Delta(6)-reductase metabolic pathway which has not been previously described, This pathway of beta-oxidatio n may limit the activity of various 5,12-diHETEs including nonenzymati c hydrolysis products of LTA(4) and also the recently described B-4-is oleukotrienes.