Apparent involvement of phospholipase A2, but not protein kinase C, in the pro-oxidative interactions of clofazimine with human phagocytes.
The anti-leprosy agent, clofazimine, at concentrations of 0.1-5 micrograms/ml caused a dose-related, stimulus-non-specific (N-formyl-methionyl-leucyl-phenylalanine, calcium ionophore, opsonised zymosan, arachidonic acid and phorbol myristate acetate) potentiation of superoxide generation by human neutrophils in vitro without affecting basal oxidative responses. The pro-oxidative interactions of clofazimine with neutrophils were eliminated by the phospholipase A2 inhibitor 4-p-bromophenacyl bromide but not by the protein kinase C (PKC) inhibitor H-7. In support of these observations clofazimine promoted the release of radiolabeled arachidonic acid from neutrophil membrane phospholipids but did not influence the activity of PKC in cytosolic extracts of neutrophils or of purified PKC from rat brain. Pro-oxidative interactions of clofazimine with human phagocytes may contribute to the intraphagocytic antimycobacterial activity of this agent.
Anderson
R
R
Department of Medical Microbiology, University of Pretoria, Republic of South Africa.
Beyers
A D
AD
Savage
J E
JE
Nel
A E
AE
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000098:Acetophenones / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002991:Clofazimine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D013481:Superoxides / Q000097:blood
D000098:Acetophenones; D001095:Arachidonic Acids; D007546:Isoquinolines; D010879:Piperazines; D013481:Superoxides; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002991:Clofazimine; D011493:Protein Kinase C; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; C006821:4-bromophenacyl bromide