title: Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C(4) synthase in human blood cells.
abstract: The sesquiterpene lactone helenalin, which can be isolated from several plant species of the Asteraceae family, is a potent anti-inflammatory and antineoplastic agent. In agreement, alcohol extracts of these plants are used for local external treatment of inflammatory conditions. Since leukotrienes are important mediators in inflammatory processes, the inhibitory effects of helenalin and some derivatives on leukotriene (LT) biosynthesis were studied. Treatment of human platelets with helenalin provoked irreversible inhibition of LTC(4) synthase in a concentration- and time-dependent manner with an IC(50) of 12 microM after a 60 min preincubation. 11alpha,13-Dihydrohelenalin acetate was less potent. Interestingly, individual donors could be divided into two distinct groups with respect to the efficacy of helenalin to suppress platelet LTC(4) synthase. In human granulocytes, helenalin inhibited both the 5-lipoxygenase (IC(50) 9 microM after 60 min preincubation) and LTC(4) synthase in a concentration- and time-dependent fashion. In contrast, the drug was without effect on LTA(4) hydrolase. The GSH-containing adducts (2beta-(S-glutathionyl)-2,3-dihydrohelenalin and 2beta-(S-glutathionyl)-2,3,11alpha,13-tetra hydrohelenalin acetate) did not significantly inhibit LTC(4) synthase. The present results indicate a mechanism for the anti-inflammatory effect of helenalin and related compounds.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-171 77, Stockholm, Sweden. Susanne.Tornhamre@mbb.ki.se
authors.forename: S
authors.initials: S
authors.lastname: Tornhamre
authors.forename: T J
authors.initials: TJ
authors.lastname: Schmidt
authors.forename: B
authors.initials: B
authors.lastname: Näsman-Glaser
authors.forename: I
authors.initials: I
authors.lastname: Ericsson
authors.lastname: Lindgren JA
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D004347:Drug Interactions; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D017572:Leukotriene A4 / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane
chemical_list: D007476:Ionophores; D017572:Leukotriene A4; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D016718:Arachidonic Acid; D017997:Leukotriene C4; C026745:plenolin; D000001:Calcimycin; C001329:helenalin; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase