INFLUENCE OF THE DOSE LEVELS OF COCARCINOGEN FERRIC-OXIDE ON THE METABOLISM OF BENZO[A]PYRENE BY PULMONARY ALVEOLAR MACROPHAGES IN SUSPENSION-CULTURE

The concurrent administration of a cocarcinogenic carrier particle suc h as ferric oxide (Fe2O3) and the polycyclic aromatic hydrocarbon lung carcinogen benzo[a]pyrene (BaP) results in a decreased latency and an increased incidence in the production of lung tumors in hamsters comp ared to the administration of BaP alone. The pulmonary alveolar macrop hage (AM), the primary lung defense cell has been shown to endocytize BaP, metabolize BaP to a more biologically active form, and then relea se the metabolites. Therefore, a study was undertaken to determine in a dose-response manner the effect of AM phagocytosis of a carrier part icle (Fe2O3) on the metabolism of a carcinogen (BaP) and on the produc tion of reactive oxygen. The AM were lavaged from hamsters and culture d in suspension 2.5 x 10(6) cells/vial) with BaP (62.5 nmol, C-14 labe led) alone or adsorbed onto 0.5, 1.0, or 2.0 mg Fe2O3 in the presence of cytochrome c. Following separate ethyl acetate extractions of the A M and medium, the metabolites were isolated by high-performance liquid chromatography (HPLC) and quantified by liquid scintillation spectrom etry. The production of superoxide anions was monitored by the reducti on of cytochrome c. Concurrent exposure of AM to BaP-coated Fe2O3 resu lted in a significant increase in the amount of BaP metabolites and su peroxide anions produced with dose of Fe2O3. The following metabolites were identified in both the medium and the AM. 9,10-dihydrodiol, 7,8- dihydrodiol, 4,5-dihydrodiol, 9-hydroxy, 3-hydroxy, and 3,6-quinone. I n general, the 7,8-dihydrodiol, which is considered to be the precurso r of the ultimate carcinogenic metabolite of BaP, and superoxide anion s, which have been shown to produce localized lipid peroxidation and e dema in vivo, were significantly enhanced (p = .05, Duncan's multiple comparison test) in AM exposed to all doses of Fe2O3 when compared to AM exposed to BaP alone. This Fe2O3 dose-related enhancement of supero xide anion production is indicative of increased endocytic capacity re sulting in a greater amount of total metabolites being produced, in pa rticular, the dihydrodiols of BaP, which are considered to be products of the active metabolic pathway of BaP