Conversion of stereoisomers of leukotriene B4 to dihydro and tetrahydro metabolites by porcine leukocytes.

We have previously shown that porcine leukocytes convert leukotriene B4 (LTB4) to two major products, 10,11-dihydro-LTB4 and 10,11-dihydro-12-oxo-LTB4. Although we did not detect these products after incubation of LTB4 with human polymorphonuclear leukocytes, these cells converted 12-epi-6-trans-LTB4 to the corresponding 6,11-dihydro metabolite (i.e., there appeared to be a shift in the positions of the remaining double bonds). The objective of the present investigation was to determine whether 6-trans isomers of LTB4 are metabolized by porcine leukocytes by a pathway similar to LTB4, or whether they are metabolized by a pathway analogous to that in human leukocytes. We found that 6-trans-LTB4 and 12-epi-6-trans-LTB4 are metabolized more much extensively than LTB4 by porcine leukocytes. 6-trans-LTB4 appears to be converted by two different reductase pathways to two dihydro products differing in the positions of the two remaining double bonds between carbons 5 and 12. Dihydro-12-oxo and dihydro-5-oxo metabolites are also formed from this substrate. Porcine leukocytes also convert 6-trans-LTB4, presumably by a combination of the above two pathways, to tetrahydro, tetrahydro-12-oxo and tetrahydro-5-oxo metabolites, none of which possesses any conjugated double bonds. 12-epi-6-trans-LTB4 is also converted to tetrahydro metabolites by these cells. Experiments with deuterium-labeled 6-trans-LTB4 indicated that the deuterium in the 5-position was almost completely lost during the formation of tetrahydro-6-trans-LTB4, whereas about 80-85% of the deuterium in the 12-position was lost, suggesting a requirement for a 5-oxo intermediate. As with LTB4, 12-epi-8-cis-6-trans-LTB4, the product of the combined actions of 5-lipoxygenase and 12-lipoxygenase, was converted principally to dihydro and dihydro-12-oxo metabolites. Only a relatively small amount of the tetrahydro metabolite was detected.