THE EFFECT OF INHIBITORS OF FREE-RADICAL GENERATING ENZYMES ON LOW-DENSITY-LIPOPROTEIN OXIDATION BY MACROPHAGES

Oxidised low-density lipoprotein (LDL) produced by the action of arter ial cells, including macrophages, has been implicated in atheroscleros is. We have investigated the effect of inhibitors of various cellular free-radical generating enzymes on macrophage-mediated LDL oxidation. Xanthine oxidase and nitric oxide synthase are not responsible for LDL modification by resident mouse peritoneal macrophages. Eicosatetrayno ic acid, a lipoxygenase inhibitor, produced a dose-dependent irreversi ble inhibition of macrophage modification of LDL, but at concentration s rather close to those toxic to the cells. Diphenyl and diphenylene i odonium, NADPH oxidase and mitochondrial electron transport inhibitors , inhibited macrophage oxidation of LDL, at concentrations that were n ot obviously toxic. This suggests that NAPDH oxidase, or some other fl avin nucleotide-dependent process, may be involved in LDL oxidation by macrophages. Wortmannin and thiopropionic acid dilauryl ester did not inhibit LDL oxidation, suggesting that inhibition of NADPH oxidase ma y not be the means by which the iodonium compounds inhibit LDL oxidati on. Macrophages from C3H/HeJ mice, which lack receptors for lipopolysa ccharide, modified LDL normally, suggesting that the inadvertent primi ng of resident macrophages by traces of lipopolysaccharide bound to LD L was not involved in LDL oxidation.