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Metabolism and Covalent Binding of [³H]Benzo(a)pyrene by Isolated Perfused Lungs and Short-Term Tracheal Organ Culture of Cigarette Smoke-exposed Rats¹

Department of Physiology, University of Turku, FIN-20520, Turku 52, Finland [P. U., J. H., E-M. S., N. S.]; Department of Biochemistry, University of Surrey, Guildford GU2 5XH Surrey, England [G. M. C.]; and Department of Pharmacology, University of Oulu, FIN-90220, Oulu 22, Finland [O. P.]

The metabolism and covalent binding of the environmental carcinogen benzo(a)pyrene, a constituent of cigarette smoke, has been determined in isolated perfused lungs of sham- and cigarette smoke-exposed and 3-methylcholanthrene-pretreated male Wistar rats. Rats were exposed to cigarette smoke for 1 hr daily for either 1 or 10 days. Benzo(a)pyrene (2 nmoles) was instilled intratracheally, and metabolites in lungs and a nonrecirculating perfusate were determined. Benzo(a)pyrene was metabolized by isolated perfused lungs of sham-, cigarette smoke-exposed, and 3-methylcholanthrene-treated animals to ethyl acetate-soluble metabolites, which cochromatographed with 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene, 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, 4,5-dihydro-4,5-dihydroxybenzo(a)-pyrene, and 3-hydroxybenzo(a)pyrene. An unidentified metabolite (Y) migrating between 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene and 3-hydroxybenzo(a)pyrene was observed in perfusates from lungs of animals that had been exposed either to cigarette smoke or 3-methylcholanthrene. Metabolite production was significantly increased by exposure to either cigarette smoke or 3-methylcholanthrene. Tracheas of sham and smoke-exposed animals also converted benzo(a)pyrene to metabolites that cochromatographed with reference dihydrodiols and 3-hydroxybenzo(a)pyrene; however, no increase in metabolite production was observed in the smoke-exposed animals. Dihydrodiols were the major ethyl acetate-soluble metabolites formed by the trachea, whereas 3-hydroxybenzo(a)pyrene was the major metabolite formed in lung perfusions. After intratracheal instillation of [³H]benzo(a)pyrene, the amount of covalently bound radioactivity was significantly increased in the lungs of animals exposed to cigarette smoke compared to the corresponding sham-exposed animals.

¹ This investigation was supported in part by NIH Grant AM-06018-15 and by grants from the Medical Research Council and Cancer Research Campaign of Great Britain, the Foundation of the University of Turku and the Emil Aaltonen Foundation, Finland, and from the Juho Vainio Foundation, Finland.

² Recipient of a Royal Society European Science Exchange Programme Grant. To whom requests for reprints should be addressed.

³ Present address: NIH, National Institute of Child Health and Human Development, Developmental Pharmacology Branch, Bethesda, Md. 20014.

Received 12/20/76. Accepted 4/14/77.