IMPAIRMENT OF HUMAN NEUTROPHIL OXIDATIVE BURST BY POLYCHLORINATED-BIPHENYLS - INHIBITION OF SUPEROXIDE-DISMUTASE ACTIVITY

We report evidence of a novel mechanism by which polychlorinated biphe nyls might act as potent inducers of inflammation, Aroclor 1242 (A1242 ), a polychlorinated biphenyl mixture, and 2,2',4,4'-tetrachlorobiphen yl (PCB47), a constituent of A1242 that produces the same patterns of effects, impaired the oxidative burst of human neutrophils by inhibiti ng the antioxidant enzyme superoxide dismutase, which converts O-2(-) to H2O2. Pre-incubation of neutrophils with A1242 or PCB47 before stim ulation with phorbol 12-myristate 13-acetate heightened the respirator y burst, producing a significant increase in intracellular O-2(-) prod uction along with a significant decrease in H2O2 production compared w ith unexposed agonist-stimulated neutrophils. This was also evident in a physiologically relevant situation in which neutrophils pre-incubat ed with A1242 were subsequently stimulated with a combination of N-for myl-L-methionyl-L-leucyl-L-phenylalanine and tumor necrosis factor-alp ha. Incubation of bovine copper-zinc superoxide dismutase (EC 1.15.1.1 ) with A1242 or PCB47 in a cell-free system reversed the enzyme-mediat ed inhibition of 6-hydroxydopamine autoxidation, indicating that polyc hlorinated biphenyl inhibited superoxide dismutase activity. Low super oxide dismutase activity in neutrophils leads to imbalances between pr oduction of free radicals and antioxidant defense mechanisms, which ca n in turn induce tissue damage and hasten the onset of neutrophil apop tosis.