Inhibition of leukotriene synthesis by azelastine.
BACKGROUND
Azelastine, oxatomide, and ketotifen are used for patients with allergic diseases. These drugs inhibit the release of chemical mediators including the leukotrienes; however, the mechanism involved is unclear.


OBJECTIVE
To clarify the mechanism of inhibition, we investigated the effects of three drugs on the function of phospholipase A2, 5-lipoxygenase, leukotriene C4 synthase, and leukotriene A4 hydrolase, which are all catabolic enzymes involved in synthesizing leukotriene C4 and leukotriene B4 in rat basophilic leukemia (RBL)-1 cells.


RESULTS
The production of leukotriene C4 and leukotriene B4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C4 and leukotriene B4 when cells were stimulated with A23187. All three drugs also inhibited the A23187-stimulated release of 3H-arachidonic acid from membrane phospholipids. Azelastine inhibited the production of leukotriene C4, but not leukotriene B4, when either arachidonic acid or leukotriene A4 free acid was used as the substrate in our cell free system. Oxatomide and ketotifen did not inhibit the synthesis of either leukotriene C4 or leukotriene B4 in the same cell free study.


CONCLUSIONS
Results indicated that oxatomide and ketotifen inhibit the production of leukotriene C4 and leukotriene B4 by inhibiting phospholipase A2 activity, whereas, azelastine inhibits the leukotriene C4 production by inhibiting phospholipase A2 and leukotriene C4 synthase.
Hamasaki
Y
Y
Department of Pediatrics, Saga Medical School, Japan.
Shafigeh
M
M
Yamamoto
S
S
Sato
R
R
Zaitu
M
M
Muro
E
E
Kobayashi
I
I
Ichimaru
T
T
Tasaki
H
H
Miyazaki
S
S
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects; D015471:Leukemia, Basophilic, Acute / Q000201:enzymology / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010793:Phthalazines / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D018926:Anti-Allergic Agents; D016859:Lipoxygenase Inhibitors; D010793:Phthalazines; D007975:Leukotriene B4; D017997:Leukotriene C4; D000001:Calcimycin; D005982:Glutathione Transferase; D010741:Phospholipases A; D054467:Phospholipases A2; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C043134:leukotriene A4 hydrolase; C020976:azelastine