Differential effects of putative lipoxygenase inhibitors on arachidonic acid metabolism in cell-free and intact cell preparations.

The effects of nordihydroguairetic acid (NDGA), 3-amino-1-trifluoromethyl-)-phenyl-2-pyrazoline (BW755c), eicostatetraynoic acid (ETYA), phenidone, quercetin, and indomethacin (INDO) on the synthesis of 15-hydroxyeicosatatetraenoic acid (15-HETE) from soybean 15-lipoxygenase, leukotriene B4 (LTB4) from 5-lipoxygenase, and prostaglandin E2 (PGE2) from cyclooxygenase enzymes of rat neutrophils and mouse peritoneal macrophages were investigated. All of the drugs caused a dose-related inhibition of increased oxygen consumption by soybean 15-lipoxygenase in the presence of arachidonic acid and the rank order of potency was phenidone greater than or equal to BW755c greater than ETYA greater than quercetin greater than NDGA greater than indomethacin. The reduction in oxygen consumption correlated with a reduction of 15-HETE formation as identified by high-performance liquid chromatography. Apart from indomethacin, these drugs were also effective against the rat neutrophil 5-lipoxygenase, although the rank order of potency did not correlate with that obtained with soybean 15-lipoxygenase. Furthermore, in both A23187-activated rat neutrophils and zymosan-activated mouse peritoneal macrophages the synthesis of prostaglandins was inhibited by all of these drugs. In the neutrophils, the rank order of potency was INDO greater than ETYA greater than BW755c greater than quercetin greater than NDGA greater than phenidone, whereas in mouse peritoneal macrophages, the order was INDO greater than ETYA greater than BW755c greater than NDGA greater than quercetin greater than phenidone. These results suggest that putative lipoxygenase inhibitors exhibit both qualitative and quantitative differences in their effects on both lipoxygenases and cyclooxygenases.