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The Effects of Cigarette Smoke on the Metabolism of [³H]Benzo(a)pyrene by Rat Lung Microsomes¹

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

The metabolism of [³H]benzo(a)pyrene and the activities of specific enzymes involved in its further metabolism were studied in lung microsomes from sham- and cigarette smoke-exposed and 3-methylcholanthrene-pretreated rats. Benzo(a)pyrene was converted into metabolites cochromatographing with reference dihydrodiols, phenols, and quinones as well as some unknown metabolites. Exposure of rats to cigarette smoke increased the formation of different metabolites from 3- to 6-fold, whether the exposure was for 1, 10, or 21 days. The metabolite patterns were similar in smoke-exposed and 3-methylcholanthrene-pretreated rats, but 3-methylcholanthrene pretreatment caused a greater increase in metabolite production.

Pulmonary aryl hydrocarbon hydroxylase activity was increased from 3- to 6-fold after smoke exposure. The activity of epoxide hydratase (substrate: styrene oxide) was decreased after 1 day of smoke exposure and did not change after exposure for 10 or 21 days. Glutathione S-transferase activity (substrate: styrene oxide) increased after 1 and 10 days of smoke exposure. No significant changes could be seen in the activity of uridine diphosphate glucuronosyltransferase (substrate, 4-methylumbelliferone).

Isolated perfused rat lungs and lung microsomes convert benzo(a)pyrene to similar metabolites, but differences were observed in both the absolute and relative amounts of different metabolites. 9,10-Dihydro-9,10-dihydroxybenzo(a)pyrene and 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene were the major dihydrodiols formed in perfusion experiments, whereas 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene was the major metabolite in microsomes. This difference was probably due to differing rates of further conjugation of primary metabolites in the isolated perfused lungs.

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

² Present address: NIH, National Institute of Child Health and Human Development, Developmental Pharmacology Branch, Bethesda, Md. 20014.

³ To whom requests for reprints should be addressed.

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