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 such 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 compared to the administration of BaP alone. The pulmonary alveolar macrophage (AM), the primary lung defense cell, has been shown to endocytize BaP, metabolize BaP to a more biologically active form, and then release the metabolites. Therefore, a study was undertaken to determine in a dose-response manner the effect of AM phagocytosis of a carrier particle (Fe2O3) on the metabolism of a carcinogen (BaP) and on the production of reactive oxygen. The AM were lavaged from hamsters and cultured in suspension (2.5 x 10(6) cells/vial) with BaP (62.5 nmol, 14C labeled) 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 AM and medium, the metabolites were isolated by high-performance liquid chromatography (HPLC) and quantified by liquid scintillation spectrometry. The production of superoxide anions was monitored by the reduction of cytochrome c. Concurrent exposure of AM to BaP-coated Fe2O3 resulted in a significant increase in the amount of BaP metabolites and superoxide 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. In general, the 7,8-dihydrodiol, which is considered to be the precursor of the ultimate carcinogenic metabolite of BaP, and superoxide anions, which have been shown to produce localized lipid peroxidation and edema 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 superoxide anion production is indicative of increased endocytic capacity resulting in a greater amount of total metabolites being produced, in particular, the dihydrodiols of BaP, which are considered to be products of the active metabolic pathway of BaP.
National Institute for Occupational Safety and Health, Cincinnati, Ohio.
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Greife
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Warshawsky
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D006224:Cricetinae; D003574:Cytochrome c Group / Q000378:metabolism; D004705:Endocytosis; D005290:Ferric Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D003574:Cytochrome c Group; D005290:Ferric Compounds; D017382:Reactive Oxygen Species; C000499:ferric oxide; D001564:Benzo(a)pyrene