Characterization of 5-lipoxygenase inhibitors in biochemical and functional in vivo assays.
Several potent and selective inhibitors of 5-lipoxygenase (5-LO) have been recently developed with excellent activity in certain in vivo assays of leukotriene production. The efficacy of three such inhibitors that have been in clinical trials (zileuton, A-78773 and ZD2138) were evaluated in: 1) ex vivo whole blood assay, 2) dermal Arthus reaction, and 3) functional airway response. In addition, a model of eicosanoid production in rat lung was developed that provides a simple assay for evaluation of the biochemical efficacy of 5-LO inhibitors in the lung. Bronchoalveolar lavage of rat lung with calcium ionophore A23187 resulted in rapid and robust production of PGE2, 6-keto-PGF1 alpha, thromboxane (TxB2), and leukotriene B4 (LTB4). Supplementation of lavage fluid with archidonic acid markedly augmented production of all eicosanoids except LTB4. All three inhibitors were potent and selective blockers of LTB4 production in the ex vivo whole blood assay and in the dermal Arthus reaction. In contrast, higher doses of inhibitor were needed to block LTB4 production in the rat lung lavage model than were needed to block ex vivo whole blood LTB4 production when both end points were measured in the same animal. Similarly, zileuton and A-78733 were less effective in suppressing the functional airway response to antigen in sensitized guinea pigs, whereas both inhibitors were effective in suppressing LTB4 production in the ex vivo whole blood assay. These results demonstrate that different 5-LO inhibitors have markedly distinct efficacy for inhibition of leukotriene production, depending on the animal model.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
W G
WG
Inflammatory Diseases Research, Searle Research and Development, Skokie, Illinois, USA.
Shaffer
A F
AF
Currie
J L
JL
Thompson
J M
JM
Kim
S
S
Rao
T
T
Isakson
P C
PC
D000818:Animals; D000941:Antigens / Q000276:immunology; D001808:Blood Vessels / Q000293:injuries; D001992:Bronchoalveolar Lavage Fluid; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D000001:Calcimycin / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D011714:Pyrans / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000098:blood supply
D000941:Antigens; D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; C082739:A 78773; D000001:Calcimycin; C063449:zileuton; D006918:Hydroxyurea; D007213:Indomethacin