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Characterization of Pulmonary Arene Oxide Biotransformation Using the Perfused Rabbit Lung¹

Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Rapid arene oxide biotransformation has been suggested as a protective mechanism against the effects of polycyclic aromatic hydrocarbons. This is a report on benzo(a)pyrene 4,5-oxide biotransformation by perfused rabbit lungs. Benzo(a)-pyrene 4,5-oxide (5 µmol) was conjugated with glutathione and hydrated at rates of 23.8 ± 2.3 (S.D.) and 7.60 ± 1.14 nmol/min/g of tissue, respectively. The total rate for benzo(a)pyrene 4,5-oxide biotransformation by perfused lungs was about 3 times the estimated rate of arene oxide formation from benzo(a)pyrene found in previous studies. A high-pressure liquid chromatographic system was utilized to resolve the benzo(a)pyrene 4,5-oxide metabolites, which were tentatively identified by cochromatography with compounds of established chemical structure. It was discovered with this chromatographic system that perfused rabbit lungs produce a cysteine conjugate from benzo(a)pyrene 4,5-oxide but lacked the ability to conjugate trans-4,5-dihydro-4,5-dihydroxybenzo(a)pyrene with sulfuric or glucuronic acid at detectable rates. The trans-4,5-dihydro-4,5-dihydroxybenzo(a)pyrene could pass freely from the tissue into the perfusion medium but remained at a relatively high concentration in the lungs, possibly due to the lipophilic nature of this metabolite. The glutathione conjugate, which diffused slowly from the tissue into the perfusion medium, showed no tendency to accumulate in the tissue. Benzo(a)pyrene 4,5-oxide-derived radioactivity was covalently bound to pulmonary DNA, RNA, and protein. The relative activities of toxication/detoxication pathways, the apparent inability of pulmonary tissue to conjugate trans-4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene with sulfuric or ß-glucuronic acid, the tendency of some benzo(a)pyrene metabolites to accumulate in the tissue, and the relationship of these parameters with the susceptibility of lung to the effects of polycyclic aromatic are discussed.

¹ Supported in part by the United States Environmental Protection Agency under an interagency agreement relating to the Federal Interagency Energy/Environmental Research and Development Program.

² To whom requests for reprints should be addressed.

Received 5/17/79. Accepted 10/11/79.