Assessment of 5-lipoxygenase involvement in human monocyte-mediated LDL oxidation

Lipoxygenase (LO) activity has been implicated in the process by which activated human monocytes oxidize normal human low density lipoprotein (LDL) and render it toxic to target cells. Here we examined the role of 5-LO in activated monocyte-mediated LDL modification. Five putative inhibitors of 5-LO (A63162, CGS8515, PF5901, RG6866, and MK886) were used to determine if they prevented activated monocytes from oxidizing LDL. Only RG6866, A63162, and CGS8515 inhibited monocyte-mediated LDL oxidation. Nonspecific effects of these drugs on LDL oxidation by activated monocytes were examined. RG6866 and A63162 were both found to be general antioxidants at their effective concentrations. CGS8515 was toxic at its effective concentration. A63162, CGS8515, and RG6866 also inhibited 15-LO activity in vitro. MK886 and PF5901 did not exhibit the nonspecific effects above and did not inhibit monocyte-mediated LDL oxidation, whereas both MK886 and PF5901 inhibited production of 5-LO metabolites by activated monocytes at concentrations that had no effect on LDL oxidation by the activated monocytes. Since neither of these agents inhibited LDL oxidation, we conclude that 5-LO is not involved in human monocyte oxidation of LDL. The possibility that a cellular 12- or 15-LO is involved in human monocyte-mediated LDL oxidation remains to be evaluated.