Volume 270,
Number 34,
Issue of August 25, pp. 19845-19852, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Metabolism
of 6-trans-Isomers of Leukotriene B
in Cultured
Hepatoma Cells and in Human Polymorphonuclear Leukocytes
IDENTIFICATION OF A 
-REDUCTASE METABOLIC PATHWAY
(Received for publication, March
3, 1995; and in revised form, June 23, 1995)
Pat
Wheelan,
Robert
C.
Murphy
The intermediate metabolic events which degrade hydroxy
polyunsaturated fatty acids is largely unknown. Such molecules are
common products of lipid peroxidation and lipoxygenase catalyzed
oxidation of arachidonic acid. Metabolism of two
5,12-dihydroxyeicosatetraenoic acids, 6-trans-LTB
(leukotriene B), and
6-trans-12-epi-LTB was studied in HepG2
cells (a human-derived hepatoma cell line). Extensive metabolism was
observed with a major metabolite identified as 4-hydroxy-6-dodecenoic
acid for both epimers. Incubation of 6-trans-LTB epimers at shorter times revealed the formation of intermediate
metabolites, including 6-hydroxy-4,8-tetradecadienoic acid and
8-hydroxy-4,6,10-hexadecatrienoic acid suggesting 
-oxidation as
the major pathway leading to the formation of the common terminal
metabolite. Two additional metabolites were structurally elucidated as
5-oxo-6,7-dihydro-LTB and 6,7-dihydro-LTB which
have not been previously described. Formation of
5-oxo-6,7-dihydro-LTB and 6,7-dihydro-LTB were
also observed during metabolism of
6-trans-12-epi-LTB in human
polymorphonuclear leukocytes. Of particular interest is the metabolism
of these compounds by -oxidation from the carboxyl terminus, a
process which is not observed with leukotriene B or
leukotriene C. Identification of these metabolites
suggested the operation of the 5-hydroxyeicosanoid dehydrogenase
pathway followed by a -reductase metabolic pathway
which has not been previously described. This pathway of
-oxidation may limit the activity of various 5,12-diHETEs
including nonenzymatic hydrolysis products of LTA and also
the recently described B-isoleukotrienes.
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