An alternate mechanism for regulation of leukotriene production in leukocytes: studies with an anti-inflammatory drug, sodium diclofenac.
Sodium diclofenac, a potent cyclooxygenase inhibitor, was recently shown to inhibit arachidonic acid conversion to leukotriene products in human leukocytes. This activity was confirmed by radioimmunoassay in calcium ionophore A 23187-stimulated leukocytes isolated from the rat peritoneal cavity and human peripheral blood. Studies with rat peritoneal leukocytes revealed that this effect was not mediated by inhibition of 5-lipoxygenase or phospholipase A2, but rather through modulation of arachidonic acid uptake and release. The potency of this effect was dependent upon cell type; macrophages being more sensitive to the drug than neutrophils. In leukocytes treated with sodium diclofenac, arachidonic acid released from phospholipids in response to A 23187 challenge was reincorporated into triacylglycerols. The drug enhanced the spontaneous uptake of arachidonic acid into the cellular triacylglycerol pool and, in this manner, decreased the availability of intracellular arachidonic acid. Therefore, sodium diclofenac, in addition to inhibition of cyclooxygenase, regulates leukotriene production of inflammatory cells by a mechanism mediated in part through the redistribution of arachidonic acid in lipid pools.
Kothari
H V
HV
Research Department, CIBA-GEIGY Corporation, Summit, NJ 07901.
Lee
W H
WH
Ku
E C
EC
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001682:Biological Availability; D000001:Calcimycin / Q000494:pharmacology; D002474:Cell-Free System; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism*; D007975:Leukotriene B4 / Q000097:blood*; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000097:blood*; D014280:Triglycerides / Q000097:blood
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D009829:Oleic Acids; D013189:SRS-A; D014280:Triglycerides; D004008:Diclofenac; D007975:Leukotriene B4; D016718:Arachidonic Acid; D019301:Oleic Acid; D000001:Calcimycin