Clofazimine-mediated stimulation of prostaglandin synthesis and free radical production as novel mechanisms of drug-induced immunosuppression.
The effects of clofazamine (3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-(isopropylimino)-phenazine) at concentrations of 0.625-20 micrograms/ml on the mitogen-induced transformation, luminol-enhanced chemiluminescence, arachidonic acid metabolism and sulphydryl content of human mononuclear leucocytes (MNL) were investigated in vitro. The drug at all concentrations tested decreased MNL sulphydryl content and inhibited mitogen-induced transformation. Clofazimine increased the spontaneous luminol-enhanced chemiluminescence and activated the arachidonic acid cascade in MNL. The anti-oxidants ascorbic acid and cysteine and the prostaglandin (PG) synthesis inhibitor indomethacin were used individually and in combination to identify the primary mediators of the anti-proliferative effects of clofazimine on MNL. Combinations of an anti-oxidant with a PG synthesis inhibitor completely protected MNL from clofazimine mediated inhibition of mitogen-induced transformation. These results show that the anti-proliferative activity of clofazimine is related to both the pro-oxidative and PG synthesis enhancing effects of the drug on MNL.
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D002991:Clofazimine / Q000494:pharmacology*; D015232:Dinoprostone; D005609:Free Radicals; D006801:Humans; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000096:biosynthesis; D013189:SRS-A / Q000096:biosynthesis; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis
D005609:Free Radicals; D008934:Mitogens; D010835:Phytohemagglutinins; D011453:Prostaglandins; D011458:Prostaglandins E; D013189:SRS-A; D013438:Sulfhydryl Compounds; D013929:Thromboxane B2; D002991:Clofazimine; D015232:Dinoprostone