MECHANISM OF 5-LIPOXYGENASE INHIBITION BY ACETYL-11-KETO-BETA-BOSWELLIC ACID

The formation of 5-lipoxygenase (EC 1.13.11.34) products from endogeno us substrate by intact rat neutrophilic granulocytes and from exogenou s arachidonic acid by rat granulocyte 105,000 x g supernatants and aff inity chromatography-purified human leukocyte 5-lipoxygenase was inhib ited by acetyl-11-keto-beta-boswellic acid (IC50 values of 1.5 mu M, 8 mu M, and 16 mu M, respectively). With other pentacyclic triterpenes lacking the 11-keto function and/or the carboxyl function on ring A (e .g., amyrin and ursolic acid), no 5-lipoxygenase inhibition was observ ed. The presence of the noninhibitory pentacyclic triterpenes both in intact cells and in the cell-free system caused a concentration-depend ent reversal of the 5-lipoxygenase inhibition by acetyl-11-keto-beta-b oswellic acid, whereas the inhibitory actions of 5-lipoxygenase inhibi tors from different chemical classes (MK-886, L-739,010, ZM-230,487, a nd nordihydroguaiaretic acid) were not modified. The inhibition by ace tyl-11-keto-beta-boswellic acid and the antagonism by noninhibitory pe ntacyclic triterpenes were not due to nonspecific lipophilic interacti ons, because lipophilic four-ring compounds (cholesterol, cortisone, a nd testosterone) neither inhibited the activity of the 5-lipoxygenase nor antagonized the inhibitory action of acetyl-11-keto-beta-boswellic acid. Therefore, we conclude that acetyl-11-keto-beta-boswellic acid acts directly on the 5-lipoxygenase enzyme at a selective site for pen tacyclic triterpenes that is different from the arachidonate substrate binding site.