Involvement of leukotriene B4 in murine dermatitis models.
Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. To investigate the role of LTB4 in dermatitis, we used S-(4-dimethylaminobenzyl)-N-[(2S)-3-mercapto-2-methylpropionyl]-L- cysteine (SA6541), a potent leukotriene A4 (LTA4) hydrolase inhibitor. SA6541 inhibited LTB4 production with an IC50 value of 270 nM in vitro. 5-Hydroperoxyeicosatetraenoic acid (5-HPETE) or AA injection induced LTB4 production and neutrophil influx in mouse ear. SA6541 inhibited 5-HPETE- and AA-induced LTB4 production and neutrophil influx in mouse ear when administered orally at a dose of 50 mg/kg. SA6541 also inhibited 5-HPETE-induced prostaglandin E2 (PGE2) production, probably by an indirect effect through the inhibition of LTB4 production. These results suggest that LTB4 may be important in the pathogenesis of dermatitides such as psoriasis.
Tsuji
F
F
Discovery Research Division, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Miyake
Y
Y
Horiuchi
M
M
Mita
S
S
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000009:adverse effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003872:Dermatitis / Q000209:etiology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism*; D015289:Leukotrienes / Q000009:adverse effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR
D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D015289:Leukotrienes; C110878:SA 6541; D007975:Leukotriene B4; D016718:Arachidonic Acid; C025348:arachidonic acid 5-hydroperoxide; D004851:Epoxide Hydrolases; D003545:Cysteine; C043134:leukotriene A4 hydrolase