Prior studies with rats have suggested that sulfur dioxide (S02) may potentiate the pulmonary carcinogenicity of polycylic aromatic hydrocarbons (PAH), in particular benzo(a) pyrence (BP). Man is also exposed simultaneously to PAH and S02 in urban and pollute atmospheres, and may therefore be at increased risk from this combination. We propose to investigate whether S02 alters the pylmonary metabolism of BP so as to increase exposure of lung tissues to toxic intermediates arising from BP. We sill use the isolated, ventilated and perfused rat lung (IVPL) preparation and cultures of rat pulmonary type II cells. Radiolabeled BP will be used as a model PAH substrate, and the molecular distribution of its metabolites determined by use of high pressure liquid chromatography. Convalent binding of BP with lung macromolecules will also be determined. Varying concentrations of S02 will be added to the ventilating gas of the IVPL or of the cell cultures; and the effects on the rates of metabolism, covalent binding and BP metabolite profile will be determined. Other rats will be exposed to various concentrations of S02 or to sulfite in the drinking water, killed at specific time intervals and used for the IVPL preparation to determine the effects of in vivo exposure on BP metabolism. Similar experiments will be conducted with rats treated with 5,6-benzoflavone to induce the lung mixed-function oxidase enzymes. The risk of carcinogenesis will be assessed based on rates of metabolism, the ratio of potentially reactive to non-reactive metabolites formed, and the amount of covalent binding. We wish to test the hypothesis that on exposure to S02, sulfitolysis of oxidized glutathione (GSH) occurs and so depletes the pulmonary supply of glutathione (GSH) as to impair the detoxication of active metabolites of BP by GSH conjugation via the glutathione S-transferases. We will, therefore, assess the extent and time-course of pulmonary S-sulfonate formation following S02 exposure in whole animals, type II cells, and the IVPL, and determine what proportion of the pulmonary GSSG pool is sequestered as GS-S03. These parameters will be correlated with specific effects of S02 on BP metabolism.
| Leung, K H; Keller, D A; Menzel, D B (1989) Effect of sulfite on the covalent reaction of benzo[a]pyrene metabolites with DNA. Carcinogenesis 10:259-64 |
| Keller, D A; Menzel, D B (1989) Effects of sulfite on glutathione S-sulfonate and the glutathione status of lung cells. Chem Biol Interact 70:145-56 |
| Keller, D A; Menzel, D B (1985) Picomole analysis of glutathione, glutathione disulfide, glutathione S-sulfonate, and cysteine S-sulfonate by high-performance liquid chromatography. Anal Biochem 151:418-23 |
| Leung, K H; Post, G B; Menzel, D B (1985) Glutathione S-sulfonate, a sulfur dioxide metabolite, as a competitive inhibitor of glutathione S-transferase, and its reduction by glutathione reductase. Toxicol Appl Pharmacol 77:388-94 |
