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Inhibition in Vivo of the Formation of Adducts between Metabolites of Benzo(a)pyrene and DNA by Butylated Hydroxyanisole

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

Antioxidants have been shown to inhibit the carcinogenic effects of a variety of chemical carcinogens. For example, the phenolic antioxidant butylated hydroxyanisole (BHA) has been shown to be a potent inhibitor of benzo(a)pyrene (BP)-induced neoplasia in mouse lung and forestomach. The objective of the present study was to determine whether or not BHA, under conditions known to result in inhibition of BP-induced neoplasia, affects the formation of BP metabolite:DNA adducts. Following p.o. administration of a carcinogenic dose of [³H]BP to A/HeJ mice, radioactivity was detected in the DNA of both lung and liver. Analysis of the deoxyribonucleosides by high-pressure liquid chromatography showed that the major adduct in both tissues cochromatographed with the (±)-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEI):deoxyguanosine adduct. The 7ß,8-dihydroxy-9ß,10ß-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEII):deoxyguanosine adduct was 10 to 15% of the BPDEI adduct in both lung and liver. Another adduct, possibly derived from BP phenol(s), was also detected in lung and was 10 to 20% of the BPDEI adduct. Treatment of animals with BHA decreased the amount of the BPDEI adduct in the lung and the liver approximately 55 and 75%, respectively. The decrease in the amount of this adduct in the lung appears to correlate with the inhibition of pulmonary adenoma formation (L. W. Wattenberg, J. Natl. Cancer Inst., 50: 1541–1544, 1973; J. L. Speier, L. K. Lam, and L. W. Wattenberg, J. Natl. Cancer Inst., 60: 605–609, 1978). Thus, BHA appears to inhibit BP-induced pulmonary adenoma formation by inhibiting the amount of the BPDE:DNA adducts formed in lung. Possible mechanisms by which BHA treatment inhibits the formation of BPDE:DNA adducts are discussed.

¹ To whom requests for reprints should be addressed.

² Present address: College of Pharmacy, Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada.

³ Present address: Metabolism Section, Environmental Health Laboratory, Department of Medicine and Environmental Health, Monsanto Company, St. Louis, MO. 63110.

Received 1/ 5/81. Accepted 7/29/81.