STIMULATORY EFFECTS OF SULFUR AND NITROGEN-OXIDES ON CARCINOGEN ACTIVATION IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES

The occurrence of inflammatory processes and of cancer in the human re spiratory tract is intimately associated. One of the major factors in this is probably the recruitment of and stimulated activity of polymor phonuclear leukocytes (PML) in conjunction with the ability of these c ells to convert various carcinogens to their ultimate active metabolit es. in this study. we demonstrate that nitrite and sulfite, the major dissolution products of the environmental pollutants nitrogen dioxide and sulfur dioxide in water enhance the metabolic activation of trans- 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-dihydrodiol), the prox imal carcinogen of benzo[a]pyrene, to droxy-9,10-epoxy-7,8,9,10-tetrah ydrobenzo[a]pyrene (BPDE) and tetraols, the corresponding hydrolysis p roducts, in human PML prestimulated with 12-O-tetradecanoylphorbol-13- acetate. Nitrite was more efficient than sulfite in stimulating the fo rmation of reactive intermediates of BP-7,8-dihydrodiol in PML that co valently bind to extracellular DNA and, in particular, to intracellula r proteins. The mechanism by which sulfite stimulates the metabolism o f BP-7,8-dihydrodiol most probably involves the intermediate formation of a sulfur trioxide radical anion (SO3radical anion) the subsequent formation of the corresponding sulfur peroxyl radical anion ((OOSO3-)- O-.) in the presence of oxygen. The mechanism underlying the stimulato ry action of nitrite is less clear but the major pathway seems to invo lve myeloperoxidase. These results offer an explanation for the increa sed incidence of lung cancer in cigarette smokers living in urban area s. The major glutathione transferase (GST) isoenzyme in human PML is G ST P1-1, a Pi-class form. The GST activity of PML was found to be inve rsely correlated with the extent of binding of BP-7,8-dihydrodiol prod ucts to exogenous DNA. These results suggest that individuals exhibiti ng high GST-activity in the PML may be better protected against the ty pe of carcinogenic dealt with in this study.