Effect of phenothiazines on activated macrophage-induced luminol-dependent chemiluminescence

The inhibitory effect of some phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, promethazine and trifluoperazine) on the ability of rat peritoneal macrophages to produce O2- during phagocytosis was investigated. The superoxide radical release was estimated by measuring the luminol-dependent chemiluminescence (CL). The effect of drugs was studied in the concentration range of 0.1-100 mumol/l. Additional experiments to determine the ability of the drugs to scavenge O2- were carried out. They included measuring the effect of phenothiazines on the luminol-dependent CL in systems with enzymatically (xanthine-xanthine oxidase) and non-enzymatically (KO2) generated O2-. The ability of phenothiazines to scavenge O2- was additionally tested by a "non-luminescence" method in which the superoxide concentration was determined spectrophotometrically by the reduction of nitro blue tetrazolium to formazan. All drugs tested decreased significantly CL of stimulated macrophages at concentrations greater than 1 mumol/l. The C50 values were between 0.45 and 1.74 mumol/l. Also phenothiazines were found to act as scavengers of O2-. However, this effect occurred at significantly higher drug concentrations. The C50 values for 50% scavenging of O2- in systems with different sources of O2- were in the concentration range of 5-160 mumol/l. These results suggested that phenothiazines predominantly affected the ability of macrophages to produce O2- during phagocytosis. The findings may provide some insight into the untoward effects of the drugs tested.