title: Mechanism of 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid.
abstract: The formation of 5-lipoxygenase (EC 1.13.11.34) products from endogenous substrate by intact rat neutrophilic granulocytes and from exogenous arachidonic acid by rat granulocyte 105,000 x g supernatants and affinity chromatography-purified human leukocyte 5-lipoxygenase was inhibited by acetyl-11-keto-beta-boswellic acid (IC50 values of 1.5 microM, 8 microM, and 16 microM, 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 observed. The presence of the noninhibitory pentacyclic triterpenes both in intact cells and in the cell-free system caused a concentration-dependent reversal of the 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid, whereas the inhibitory actions of 5-lipoxygenase inhibitors from different chemical classes (MK-886, L-739,010, ZM-230,487, and nordihydroguaiaretic acid) were not modified. The inhibition by acetyl-11-keto-beta-boswellic acid and the antagonism by noninhibitory pentacyclic triterpenes were not due to nonspecific lipophilic interactions, because lipophilic four-ring compounds (cholesterol, cortisone, and 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 pentacyclic triterpenes that is different from the arachidonate substrate binding site.
authors.affiliation: Department of Pharmacology, University of Tuebingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Safayhi
authors.forename: E R
authors.initials: ER
authors.lastname: Sailer
authors.forename: H P
authors.initials: HP
authors.lastname: Ammon
mesh_terms: D000818:Animals; D006801:Humans; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D016859:Lipoxygenase Inhibitors; D014315:Triterpenes; C094432:acetyl-11-ketoboswellic acid