MECHANISMS OF CARCINOGENESIS OF DIBENZO(A,1)PYRENE

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Although health hazards associated with cigarette smoking are well-known, the carcinogens that present these hazards have not been quantitatively determined or in some cases qualitatively identified. Dibenzo[a,l]pyrene (DB[a,l]P) has been identified in the biologically active fraction of tobacco smoke condensate. We have recently found this compound to be an extremely potent carcinogen, much stronger than benzo[a]pyrene (BP), suggesting that it may represent a significant risk in cigarette smoke and other environmental pollutants. Therefore, we plan to determine the potency of DB[a,l]P by comparing its tumorigenic activity in rat mammary gland by direct application, and in rat lung by direct application to that of BP, the strongest known environmental polycyclic aromatic hydrocarbon (PAH), and 7,12-dimethylbenz[a]anthracene (DMBA), the strongest known carcinogenic PAH. To provide evidence on the mechanism of carcinogenesis of DB[a,l]P, we propose to investigate 1) whether the metabolite DB[a,l]P 11,12-dihydrodiol is a proximate tumor-initiator; 2) whether DBp[a,l[P activates ras oncogenes similarly to DMBA or BP in mouse skin, rat mammary gland and rat lung tumors by detection of a point mutated Ha-ras, Ki-ras or N-ras gene using amplification by the polymerase chain reaction and direct dideoxyribonucleotide DNA sequencing; 3) the relative reactivity of DB[a,l]P, DB[a,e]P and BP with nucleophiles in one-electron oxidation with Mn(OAc), and in electrochemical oxidation; 4) the binding of DB[a,l]P to DNA in vitro with horseradish peroxidase, prostaglandin H synthase, rat lever microsomes and rat liver nuclei by determining the level of binding and identifying the DNA adducts formed; and 5) the binding of DB[a,l]P in vivo in mouse skin, rat mammary gland and rat lung by determining the level of binding and identifying the DNA adducts formed. With this experimental approach we will assess the carcinogenic potency of DB[a,l]P vs DMBA and BP, and we will also know whether its ability to activate ras oncogenes resembles that of DMBA and BP, and we will also know whether its ability to activate ras oncogenes resembles that of DMBA or BP. Since we expect that the carcinogenicity of DB[a,l]P is similar to that of DMBA, we think our tumorigenicity studies of DB[a,l]P will demonstrate that this PAH represents a significant human health hazard in cigarette smoke and other environmental pollutants. The data obtained from the chemistry, tumorigenicity, DNA-binding studies and oncogene activation will provide significant clues concerning the mechanism of carcinogenesis of DB[a,l]P.