Stimulus-dependent effects of CI-986 on arachidonic acid metabolism by human neutrophils.
CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3, 4-thiadizole-2(3H)-thione, choline salt) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B4 (LTB4) release in response to calcium ionophore A23187 was 15 to 35 fold greater than the responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP) or serum-opsonized zymosan (SOZ), respectively, while the thromboxane B2 (TXB2) release response was similar for the three stimuli tested. CI-986 inhibited the release of LTB4 and TXB2 in response to A23187 with IC50s of 63.4 and 1.6 microM, respectively. In comparison, the compound inhibited SOZ-stimulated LTB4 release with an IC50 of 11.2 microM, while having no effect on TXB2 at concentrations up to 100 microM. Conversely, CI-986 inhibited FMLP-stimulated LTB4 release by 42% at 100 microM, while inhibiting TXB2 release with an IC50 of 0.13 microM. These results demonstrate a stimulus-dependent inhibitory effect of CI-986 on human neutrophil eicosanoid metabolism.
Wright
C D
CD
Department of Immunopathology, Parke-Davis Pharmaceutical Research, Division of the Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Kennedy
J A
JA
Kuipers
P J
PJ
Ferin
M A
MA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D016014:Linear Models; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D013830:Thiadiazoles; C080863:CI 986; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D013929:Thromboxane B2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015054:Zymosan